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. Author manuscript; available in PMC: 2019 Nov 1.
Published in final edited form as: Can J Physiol Pharmacol. 2019 Mar 9;97(7):589–599. doi: 10.1139/cjpp-2018-0570

Tβ4–Ac-SDKP pathway: Any relevance for the cardiovascular system?

Kamal M Kassem 1,2, Sonal Vaid 3,4, Hongmei Peng 5, Sarah Sarkar 6, Nour-Eddine Rhaleb 7,8
PMCID: PMC6824425  NIHMSID: NIHMS1040886  PMID: 30854877

Abstract

The last 20 years witnessed the emergence of the thymosin β4 (Tβ4)–N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) pathway as a new source of future therapeutic tools to treat cardiovascular and renal diseases. In this review article, we attempted to shed light on the numerous experimental findings pertaining to the many promising cardiovascular therapeutic avenues for Tβ4 and (or) its N-terminal derivative, Ac-SDKP. Specifically, Ac-SDKP is endogenously produced from the 43-amino acid Tβ4 by 2 successive enzymes, meprin and prolyl oligopeptidase. We also discussed the possible mechanisms involved in the Tβ4–Ac-SDKP-associated cardiovascular biological effects. In infarcted myocardium, Tβ4 and Ac-SDKP facilitate cardiac repair after infarction by promoting endothelial cell migration and myocyte survival. Additionally, Tβ4 and Ac-SDKP have antifibrotic and anti-inflammatory properties in the arteries, heart, lungs, and kidneys, and stimulate both in vitro and in vivo angiogenesis. The effects of Tβ4 can be mediated directly through a putative receptor (Ku80) or via its enzymatically released N-terminal derivative Ac-SDKP. Despite the localization and characterization of Ac-SDKP binding sites in myocardium, more studies are needed to fully identify and clone Ac-SDKP receptors. It remains promising that Ac-SDKP or its degradation-resistant analogs could serve as new therapeutic tools to treat cardiac, vascular, and renal injury and dysfunction to be used alone or in combination with the already established pharmacotherapy for cardiovascular diseases.

Keywords: Ac-SDKP, thymosin beta 4, cardiovascular, renal, angiotensin-converting enzyme

General aspects of thymosin β4 (Tβ4)–N-acetylseryl-aspartyl-lysyl-proline (Ac-SDKP)

Tβ4 is an endogenous 43-amino acid peptide, first isolated in the thymus and subsequently found in the blood circulation, urine, and various organs, including the heart and kidneys (Mora et al. 1997). Tβ4 was best known for its G-actin sequestering protein, and thus preventing actin polymerization and ensuring the availability of an optimal amount of actin monomer for rapid filament elongation (F-actin formation) when it is needed for specific cell activity (Cavasin 2006). However, it became evident that Tβ4 has numerous biological functions, including stimulation of cell migration, angiogenesis, cell survival, tissue regeneration, and inhibition of inflammation (Crockford et al. 2010). Tβ4 is the precursor of Ac-SDKP because it contains the Ac-SDKP sequence in its NH2-terminal (Hannappel 2010). Our group has shown previously that Ac-SDKP is released from Tβ4 by the peptidases present in kidney homogenates, and specific inhibitors of prolyl oligopeptidase (POP) block this release (Cavasin et al. 2004). However, POP has a structural characteristic that prevents the enzyme from hydrolyzing peptides containing more than 30 amino acids (Polgár 2002), meaning that larger peptides and proteins are resistant to POP hydrolysis. Therefore, prior to Ac-SDKP release via POP cleavage, Tβ4 must undergo hydrolysis by a newly described peptidase, meprin α (Kumar et al. 2016).

Tβ4 has several biological functions that have been reported in numerous studies. In permanently ligated mouse and ischemia–reperfusion pig models, Tβ4 stimulated myocardial cell migration, promoted angiogenesis and survival of cardiomyocytes, and decreased inflammation, thus improving cardiac function (Hinkel et al. 2008). We have also reported that T4, at a dose that is unable to generate optimal circulating Ac-SDKP concentrations (Rhaleb et al. 2001b), prevents cardiac rupture and improves cardiac function post-myocardial infarction (MI) via its anti-inflammatory, proangiogenic, and anti-apoptotic actions in a murine model of acute MI (Peng et al. 2014). Comparable results are obtained when Ac-SDKP was used instead of Tβ4 (Peng et al. 2019, in press). The MI model in rodents shares both clinical and pathological features of post-MI with changes found in human hearts, including cardiac rupture and dysfunction (Bock-Marquette et al. 2004). Thus, Tβ4 could be used as an alternative therapy in preventing cardiac rupture and restoring cardiac function in patients with MI.

Synthesis and degradation

Tβ4 is a naturally occurring peptide consisting of 43 base pairs of amino acids and generates the N-terminal tetrapeptide AcSDKP (Kumar et al. 2016; Ma and Fogo 2009). Ac-SDKP is widely found in mammalian organs, plasma, urine, and mononuclear cells (Mora et al. 1997; Roth et al. 1999). Like Tβ4, Ac-SDKP has anti-inflammatory and antifibrotic properties. For example, they have been shown to reduce tissue invasion by detrimental inflammatory cells, and collagen deposition in the hypertension, diabetes, renal, and cardiovascular diseases (Cavasin 2006). Until recently, how Ac-SDKP was liberated from Tβ4 was unknown. A peptidase database revealed to us that meprin-α metalloprotease could hydrolyze Tβ4 first by releasing NH2-terminal intermediate peptides that are less than 30 amino acids. Then POP hydrolyzes the intermediate peptides to release Ac-SDKP (Kumar et al. 2016; Ma and Fogo 2009). Indeed, actinonin, a specific inhibitor for meprin-α, blocked both in vivo and in vitro generation of Tβ4 fragments, including the N-terminal sequence Ac-SDKP. Thus, both meprin-α metalloprotease and POP are needed for Ac-SDKP to be released from Tβ4 (Fig. 1).

Fig. 1.

Fig. 1.

Amino acid sequence of thymosin β4 (Tβ4) showing the putative meprin-α cleavage sites. Peptides were released after Tβ4 was incubated with recombinant meprin-α and analyzed by a liquid chromatography – mass spectrometer. Meprin-α cleavage sites are marked by solid arrows. Four NH2-terminal intermediate peptides <30 amino acids released from Tβ4 by meprin-α are shown. Prolyl oligopeptidase (POP) active site is indicated by a solid triangle.

Angiotensin-converting enzyme (ACE) is an essential enzyme of the renin–angiotensin system (RAS). Renin first produces angiotensin (Ang) I from angiotensinogen, and then ACE cleaves Ang I releasing the endogenous agonist Ang II (Carretero et al. 2009). The ACE protein is a single cell surface zinc metallopeptidase chain, composed of 2 separate and independent catalytic domains. Each domain contains the zinc-binding site HEMGH. These domains, called N- and C-domains, have a high conservation of sequence and exon structure, which suggest that they originated from a gene duplication event during the course of evolution (Bernstein et al. 2011). The C-domain of ACE plays the key role in the conversion of Ang I to Ang II, whereas the N-domain is responsible for the degradation of other peptides such as the antifibrotic peptide Ac-SDKP (Bernstein et al. 2011). Selective inhibition of the ACE N-domain by the phosphinic peptide RXP 407 (Junot et al. 2001) or specific gene deletion of the ACE N-domain has resulted in significant and substantial increases of circulating concentrations of Ac-SDKP without diminishing the pressor effects of Ang I (Bernstein et al. 2011; Fuchs et al. 2004). Therefore, one cannot exclude the participation of endogenous Ac-SDKP in the anti-inflammatory and antifibrotic beneficial effects of ACE inhibitor (ACEI) in the cardiovascular system and kidneys by increasing circulating and tissue levels of endogenous Ac-SDKP (Romero et al. 2017). To further document the role of Ac-SDKP in the beneficial effects of ACE inhibition, we used a model of mineralocorticoidsalt- or Ang-II-induced hypertension in rats treated with the ACEI either alone or combined with a blocking monoclonal antibody (mAb) to Ac-SDKP (Peng et al. 2005, 2007). In these studies, we reported that mAb-anti-Ac-SDKP was able to block the antifibrotic and anti-inflammatory effects of ACEI captopril without affecting blood pressure or cardiac hypertrophy, letting us to conclude that those beneficial effects of ACE inhibition are in part due to protection of endogenous Ac-SDKP from hydrolysis. Others have used POP inhibitor to demonstrate the key role played by Ac-SDKP in the protective effects of ACEIs; indeed, Li et al. have shown that inactivation of POP by selective inhibitor S-17092 reduced the formation of Ac-SDKP and blocked the protective effect mediated by the N-terminal catalytic site of ACE in a model of bleomycininduced lung fibrosis via Ac-SDKP (Li et al. 2010). Similarly, Zuo et al. found that the renal protective effects of Tβ4 could be almost fully opposed by treatment of animals under the unilateral ureter obstruction-induced nephritis with a POP inhibitor, indicating again the important role played by Ac-SDKP in the Tβ4 effects (Zuo et al. 2013).

Tβ4 and fragment biology: endogenous regulation in health and during disease (Fig. 2)

Fig. 2.

Fig. 2.

Schematic diagram of sequential hydrolysis of thymosin β4 (Tβ4). In the first step, meprin-α hydrolyzes Tβ4 into NH2-terminal intermediate peptide(s) <30 amino acids. The second step involves prolyl oligopeptidase (POP) hydrolysis of the intermediate peptide(s) that releases N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Tβ4 and Ac-SDKP, via their putative receptors, provide renal and cardiac protection by reducing inflammation and fibrosis and promoting angiogenesis. ACE, angiotensin-converting enzyme.

A study using short hairpin (sh) RNA knockdown of Tβ4 specifically in an Nkx2.5-Cre expression domain resulted in significant cardiac developmental defects. Tβ4 is pivotal in restoring pluripotency and triggering differentiation of fibroblasts, smooth muscle cells, and endothelial cells (Banerjee et al. 2012). Tβ4 was also found to be a regulator of heart valve formation in zebrafish embryos (Shin et al. 2014). Additionally, a recent study demonstrated that mice with global or cardiac-specific Tβ4 knockout did not exhibit any significant embryonic or adult cardiovascular phenotype; had no deleterious effects on angiogenesis; and did not have any noticeable histological defects, cardiac function, or age-related decline in cardiovascular function (Banerjee et al. 2012; Smart et al. 2007). However, Tβ4 deficiency does result in exacerbated renal and cardiac injury and dysfunction in Ang-II-induced hypertension. Whether this effect is due to lack of Tβ4 per se or deficiency in production of Ac-SDKP is awaiting further investigations (Kumar et al. 2018).

Ac-SDKP has protective effects in hypertensive kidney disease models of glomerulosclerosis. Our laboratory has shown that AcSDKP prevents increased collagen deposition and cell proliferation in the heart and kidney in aldosterone-salt hypertensive rats (Peng et al. 2001). Moreover, endogenous Tβ4 is upregulated in the kidney ischemia–reperfusion model (Liao et al. 2010). We found that Ac-SDKP greatly attenuates albuminuria and renal fibrosis; it improves renal function in rats with 5/6th nephrectomy (Liao et al. 2010). Our laboratory further investigated the roles of Tβ4 and Ac-SDKP in modulating early versus late tubulointerstitial fibrosis. We demonstrated that Tβ4 is upregulated in kidneys after obstructive injury, along with occasional tubular cells and increased numbers of infiltrating macrophages, fibroblast proliferation, and myofibroblasts differentiation. We also showed that exogenous administration of Tβ4 plus POP inhibitor, which prevents the metabolism of Tβ4 to Ac-SDKP, exacerbated both early and late interstitial fibrosis in mice, indicating a crucial role by Ac-SDKP in the protective effects of Tβ4 (Cavasin et al. 2004, 2007). In contrast, Ac-SDKP treatment decreased both early and late fibrosis with less total collagen and fibronectin deposition, decreased myofibroblasts and monocyte/macrophages, and suppressed profibrotic factors, plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor (TGF)-β1 (Zuo et al. 2013).

In the normal physiologic state of the kidneys, there is undetectable fibrosis and PAI-1; however, PAI-1 is increased in patients who suffer from diabetic nephropathy and arterio-nephrosclerosis (Ma and Fogo 2009). There are studies that showed that Ang II upregulates PAI-1 gene expression by the AT1 receptor, because all these effects were specifically blocked by an AT1 receptor antagonist. Moreover, patients with primary hyperaldosteronism had elevated PAI-1 antigen, and aldosterone induced in vitro PAI-1 expression via the glucocorticoid response element in the PAI- promoter (Brown et al. 2000). Interestingly, Ac-SDKP inhibited TGF-β1-induced PAI-1 and α2 type collagen in mesangial cells in vitro, and ameliorated renal insufficiency and mesangial expansion in the db/db mouse model of diabetes (Ma and Fogo 2009).

Tβ4–Ac-SDKP and ACE

It is well established that Ac-SDKP is almost exclusively degraded by the N-domain of ACE (Azizi et al. 1996, 1997; Bernstein et al. 2011). Rats treated with captopril, an ACEI, exhibited increased plasma and urine concentrations of Ac-SDKP, which were inhibited by the co-administration of actinonin, a meprin-α metalloprotease inhibitor (Kumar et al. 2016).

Several trials (e.g., Heart Outcomes Prevention Evaluation, Survival and Ventricular Enlargement, and European Trial of Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease) have exhibited improvement in cardiovascular disease outcomes using ACEi (Rosendorff et al. 2015), while the role of Tβ4’s N-terminal fragment Ac-SDKP is not yet established in patients. However, many incidences indicate possible involvement of Ac-SDKP in the protective effects of ACEi. We have shown that treatment with ACEIs is associated with reduced degradation of Ac-SDKP and has resulted in blunted hypertension-induced inflammation and fibrosis in the heart and kidneys without affecting blood pressure or hypertrophy. These protective effects were antagonized with monoclonal antibodies against Ac-SDKP (Hrenak et al. 2015; Peng et al. 2005, 2007). Moreover, in a study of Ser333Trp ACE mutation identified in a patient of African descent who displayed unusual blood ACE kinetics with regards to N-domain-associated peptides, it was noted that the clearance of Ac-SDKP was reduced (Danilov et al. 2014). Another important study by Pokharel et al. has demonstrated that increased cardiac ACE activity by genetically overexpressing cardiac-specific ACE resulted in exaggerated increase in cardiac collagen content; this phenotype has been attributed to selectively increased degradation of endogenous Ac-SDKP, and cancellation of its inhibitory effects on the phosphorylation of TGF-β signaling molecules and its downstream signaling (Peng et al. 2005, 2007; Pokharel et al. 2004). This implies that the antifibrotic effects of ACEIs are mediated in part by increasing cardiac Ac-SDKP. In addition, Tβ4 and its cleavage product Ac-SDKP are reportedly downregulated in advanced chronic heart failure in patients and the canine experimental model of congestive heart failure (Gupta et al. 2014; Sabbah et al. 2015), indicating a substantial clinical significance of the Tβ4–Ac-SDKP pathway in cardiovascular diseases. This suggests that strategies to increase concentrations of the endogenous antifibrotic peptide Ac-SDKP or administration of Ac-SDKP analogs with higher circulating half-life would be safe and physiologically relevant.

Tβ4 is a G-actin binding protein that accelerates wound healing, decreases inflammation, and is found only in mammals (Huff et al. 2004). It was first thought to be located only in thymocytes; however, it is ubiquitously distributed in the body, including lymphocytes, macrophages, cornealcells, and the kidneys (Gómez-Márquez et al. 1989; Nathan 1987). Tβ4 is also known to increase tissue remodeling, vascular endothelial growth factor, and angiogenesis in various tissues like myocardium, cornea, and dermis. Tβ4 has been known to upregulate antioxidative enzymes in human corneal epithelial cells for protection against H2O2-induced oxidative damage (Ho et al. 2008). Others have also demonstrated that Tβ4 is upregulated in the fibrotic interstitium found in the distal and proximal tubular cells, and peritubular capillaries of the kidneys in a model of unilateral ureteral obstruction (Ma and Fogo 2009), but the significance of this finding remains to be determined and reconciled against other reports that showed rather downregulation of Tβ4 in heart failure (Gupta et al. 2014; Sabbah et al. 2015).

There is an array of chronic renal diseases that cause chronic nephropathies by damage via progressive renal scarring, fibrosis, increased blood pressure, glomerular hyperfiltration, proteinuria, and loss of renal function (Rodríguez-Lara et al. 2018). In these diseases, the RAS is activated, which releases renin from the juxtaglomerular cells in the proximal convoluted tubule of the kidneys. Renin then converts angiotensinogen (found in the liver) to Ang I, which is in turn converted to Ang II via ACE (Rodríguez-Lara et al. 2018). Ang II then increases sympathetic activity; increases tubular Na+, Cl absorption, and K+ excretion; causes the adrenal gland to release aldosterone further causing H2O retention; causes arteriolar vasoconstriction to increase blood pressure; and releases antidiuretic hormone from the posterior pituitary gland to increase H2O absorption from the collecting duct (Rodríguez-Lara et al. 2018). All these factors contribute to water and salt retention, and increases circulating volume and perfusion of the juxtaglomerular apparatus in the kidneys (Rodríguez-Lara et al. 2018).

Animal data has shown that inhibition of the RAS can ameliorate the deterioration of the kidneys in these diseases, as the RAS consist of classes of pro-fibrotic factors (van der Meer et al. 2010). The direct effects of Ang II cause increased protein ultrafiltration via ACE (Carlström et al. 2015). Large proteins are eventually lost into the urinary space, and tubulointersitial damage causes renal function to decline. Protein overload in the tubules causes tubular cells to release cytokines, chemokines, growth factors, and vasoactive substances. This leads to abnormal interstitial accumulation of inflammatory cells and interstitial fibrosis (Ma and Fogo 2009). The data suggested that chronic renal therapy with ACEI or Ang II receptor type I blockers can reverse the damaging glomerulosclerosis even in later stages of chronic kidney diseases. In addition, another murine study demonstrated that when the addition of Ang II infusion caused fibrosis, Tβ4 levels were increased (Ma and Fogo 2009). The physiological significance of such finding has not yet been explored.

Interaction of ACE or AT1 antagonist and Ac-SDKP toward therapy optimization and side effect factors

There were major findings in our laboratories that showed that mice treated with Tβ4 exhibited a reduced mortality rate because of decreased left ventricular rupture post-MI (Peng et al. 2014). We found that excessive inflammatory responses were partially prevented by Tβ4 compared with the control group (Peng et al. 2014). Tβ4 exerts anti-inflammatory actions by inhibiting proinflammatory factors such as ICAM-1 in the left ventricle and inhibiting gelatinolytic activity. Moreover, we showed that Tβ4 treatment for 5 weeks not only reduced interstitial fibrosis and increased capillary density in the myocardium, which lead to improved cardiac function, but also ameliorated left ventricle dilatation and improved cardiac function, as evidenced by an increase in ejection fraction and shortening fraction (Peng et al. 2014). Tβ4 could potentially be a therapeutic regimen for patients with acute MI.

Ac-SDKP is not only present in the spleen and thymus, but also in the lymph node where it has yet not been investigated. T4, Ac-SDKP, and its releasing enzymes meprin-α and POP were measured in the lymph nodes, thymus, spleen of Sprague-Dawley rats (Romero et al. 2017). Cell sorting was used to measure Ac-SDKP in various lymph node cell populations. The highest concentration of Ac-SDKP was found in lymph nodes, followed by testis, thymus, and spleen. Positive immunostaining of TB4 and meprin-α in multi-nucleated giant cells was found in the cortical region, septum, follicular, and germinal centers of the lymph nodes. POP staining was also positive in the cortical region. Ac-SDKP was found to be higher in the lymph nodes than in the T lymphocytes. Macrophages were found to be the main source of Ac-SDKP in the lymph nodes. This data could indicate a key role of lymph nodes and macrophages in the preventative effects of Ac-SDKP on target organ damage of the heart in patients who are also undergoing treatment with ACEIs.

Diabetes affects more than 345 million people worldwide (Forouhi and Wareham 2014). The incidence of diabetes is increasing in the United States and there are long-term complications of diabetes mellitus that includes peripheral neuropathy and diabetic nephropathy. There is no effective treatment or reversal of the progression of diabetic neuropathy. Progression to diabetic nephropathy could be controlled by ACEIs along with tight glucose control; however, there is an urgent need for novel and more efficient methods to combat peripheral neuropathy and diabetic nephropathy. Wang et al. showed that extended Tβ4 treatment of diabetic mice improves neurological function in diabetic neuropathy independent of glucose blood levels (Wang et al. 2015). There was axonal regeneration and remyelination of peripheral nerves in mice treated with Tβ4 mediated by the Ang1/Tie signaling pathway (Wang et al. 2015).

There are studies that have shown that Ac-SDKP could play a protective role against diabetic nephropathy. Ac-SDKP served as an antifibrotic factor in human mesangial cells (Pokharel et al. 2002) and ameliorated renal insufficiency and glomerulosclerosis in diabetic mice via inhibition of the TGF-β/Smad pathway (Pokharel et al. 2002). In recent studies, Nagai et al. (2014) and Nitta et al. (2016) showed that oral administration of Ac-SDKP cured kidney fibrosis. They observed that Ac-SDKP inhibited endothelial-mesenchymal transition ameliorated glomerulosclerosis and tubulointerstitial fibrosis in streptozotocin-induced diabetes in CD-1 mice. The renal protective effect of combined Ac-SDKP and ACEI was better than ACEI or Ac-SDKP alone (Nagai et al. 2014; Nitta et al. 2016). The most common therapy used to combat diabetic nephropathy is based on RAS inhibitors, which have been shown to reduce diabetic nephropathy (Piccoli et al. 2015). ACEI and Ang II type 1 receptor blockers (ARB) are 2 major drug classes prescribed to delay diabetic nephropathy progression (Piccoli et al. 2015). These 2 drug classes could show similar renoprotective effects, but also display significant differences in organ protection from diabetes-associated damage.

It is well known that the maximum dose of ACEI, which abolishes circulatory Ang II, cannot fully inhibit local Ang II production in renal tubules, and yet the ACEI captopril exhibited significant reduction of renal injury and fibrosis in a model of adriamycin-induced nephropathy in mice (Tang et al. 2008). Surprisingly, a high dose of ARB losartan alone or combined with statin therapy failed to overcome adriamycin-induced nephropathy (Tang et al. 2008). A recent meta-analysis revealed that ACEI exhibited stronger organ protection compared with ARB in patients with type 2 diabetes with nephropathy (Strauss and Hall 2018). We and others previously reported that monotherapy with ACEI, ARB, or aldosterone blocker (Anavekar and Solomon 2005; Böhm 2007; Liu et al. 2002; Marcy and Ripley 2006; Russell et al. 1993; Sato et al. 2006; Xu et al. 2002; Yang et al. 2001; Zhu et al. 2012) achieved some cardioprotective effects. Further protective effects were achieved if these monotherapies were to be combined with other drugs such as eplerenone, but not with a p38 inhibitor as we have previously shown (Liu et al. 2005; Wang et al. 2004b). Also, monotherapy with Ac-SDKP or ACEI only partly improved cardiac function (Gao et al. 2012; Leuschner et al. 2010; Liu et al. 1997, 2002, 2005; Xu et al. 2004). Moreover, results obtained by Castoldi et al., indicate that Ac-SDKP has an additive effect in reducing cardiac and renal fibrosis with respect to ACE inhibition alone (Castoldi et al. 2009, 2013). In fact, in type 1 diabetic rats, the administration of Ac-SDKP or an ACEI alone reduced cardiac TGF-β1 and Smad2/3 signaling pathway, and interstitial and perivascular fibrosis; these 2 drugs also reduced glomerular, tubulointerstitial, and perivascular fibrosis. More importantly, the concomitant administration of Ac-SDKP and ACEI resulted in a further significant reduction of cardiac and renal fibrosis when compared with ACE-l alone. Thus, Ac-SDKP, by acting directly on cardiovascular and renal damages such as tissue fibrosis, could represent a new therapeutic tool complementary to classic cardioprotective treatment based on antihypertensive drugs. However, one would stipulate that the additive effects of ACEI and Ac-SDKP could be due to the increased bioavailability of Ac-SDKP by preventing its degradation by ACE; thus, future studies are needed to investigate the therapeutic values of Ac-SDKP alone or combined with ARB, aldosterone receptor blocker, β-adrenergic receptor antagonists, or calcium channel blockers. These reports suggested that the biology of ACE in kidney fibrosis is not limited to “angiotensin-conversion” but may involve some angiotensin-independent effects.

Therapeutic considerations

These reports clearly demonstrate that Tβ4 and its N-terminal tetrapeptide derivative Ac-SDKP could be useful in the treatment of diabetic nephropathy. Tables 1 and 2 summarize most noticeable biological and therapeutic effects, together with proposed corresponding cellular signaling. It would be ideal to develop analogs of Ac-SDKP that could resist degradation, have longer circulating half-life, and that could be administered through single subcutaneous injection such as via special hydrogels for sustained release. ACE inhibition could confer renal protection in diabetic nephropathy by reducing intrarenal Ang II and augmenting AcSDKP expression.

Table 1.

Effects of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) in various diseases and experimental models.

Experimental model/
diseases
Species Dosage and
duration
Observed effects Mechanisms References

Traumatic brain injury Rats, in vivo 0.8 mg/kg per day, 3 days Improved sensorimotor functional recovery, spatial learning, reduced cortical lesion volume, and hippocampal neuronal cell loss, in the injured brain Reduced fibrin accumulation, activation of microglia/macrophages, enhanced angiogenesis, neurogenesis, and increased the number of dendritic spines Zhang et al. 2017
Embolic focal cerebral ischemia Rats, in vivo 0.8 mg/kg per day, 3 days Reduced infarct volume and neurological deficits Inactivation of TGF-β and NF-κB signaling Zhang et al. 2014
Systemic lupus erythematosus Mice, in vivo 0.8 mg/kg per day, 3 months Delayed development of severe hypertension, albuminuria, and early mortality; improved renal function Prevented glomerulosclerosis, decreased macrophage and T cell renal infiltration, prevented complement C5–9, RANTES, MCP-5 and ICAM-1 Liao et al. 2015; Nakagawa et al. 2017
Lupus nephritis MRL/lpr mice, in vivo 1.0 mg/kg per day, 12–20 weeks Reduced proteinuria and improved renal function Reduced renal T cell and macrophage infiltration; inhibited NF-κB, TNF-α, TGF-β1, α-SMA, fibronectin, and phosphoSmad2/3 Tan et al. 2012
Unilateral ureteric obstruction Mice, in vivo 1 mg/kg per day, 1 week Attenuated the gene expression of fibrotic markers Reduced expression of collagen IV, -SMA, and MCP-1 Chan et al. 2015
Unilateral ureteric obstruction Mice, in vivo 1.6 mg/kg per day, 5–14 days Reduced renal collagen 1 expression and fibrosis Reduced phosphoSmad3; reduced macrophages, PAI-1 Zuo et al. 2013
Silicosis Rats, in vivo; lung fibroblasts or HAE-A549, in vitro 0.8 mg/kg per day, 4 and 8 weeks. In vitro, 10−8 M Attenuated silicosis-induced increased lung fibrosis in vivo and TGF-β1-induced lung fibroblast differentiation; attenuated epithelial cell apoptosis Inhibited expressions of TGF-β1 and RAS signaling, inhibited myofibroblast differentiation via decreased SRF and α-SMA-positive myofibroblast localization in siliconic nodules in the lung, inhibited caspase-12 and PERK/eIF2α/CHOP (ER stress pathway Xu et al. 2012; Zhang et al. 2018
Dahl salt-sensitive rats Rats, in vivo 0.8 and 1.6 mg/kg per day, 6 weeks Prevented renal damage without affecting the blood pressure Inhibition of macrophage and T cell infiltration and renal fibrosis Worou et al. 2015
Angiotensin-II-induced hypertensive rats Rats, in vivo 0.8 mg/kg per day, 3 weeks Reduces cardiac collagen cross-linking and inflammation in angiotensin-II-induced hypertensive rats Decreased TGF-β1, LOXL1 and lymphocyte and macrophages infiltration, and NF-κB inhibition González et al. 2014
DOCA-salt hypertensive mice Mice, in vivo 0.8 mg/kg per day, 12 weeks Prevented hypertension-induced inflammatory cell infiltration, collagen deposition, nephrin downregulation, and albuminuria Decreased DOCA-salt-induced renal collagen deposition, glomerular matrix expansion, and monocyte/macrophage infiltration Rhaleb et al. 2011
Angiotensin-II-induced hypertension Rats, in vivo 0.8 mg/kg per day, 3 weeks Antifibrotic and anti-inflammation effect in thoracic aorta Enhanced expression of inhibitory Smad7 Lin et al. 2008
5/6 nephrectomy Rats, in vivo 0.8 mg/kg per day, 3 weeks Reduced albuminuria, renal inflammation, and fibrosis, and improved glomerular filtration rate Reduced inflammation and partially restored slit diaphragm nephrin protein expression in the glomerular filtration barrier Liao et al. 2010
Galactin-3-induced cardiac injury and dysfunction Rats, in vivo 0.8 mg/kg per day, 4 weeks Prevented cardiac inflammation, fibrosis, hypertrophy, and dysfunction Prevented cardiac inflammation via Gal-3, inhibited TGF-β/Smad3 signaling pathway Liu et al. 2009
Type 1 diabetes Rats, in vivo 1 mg/kg per day, 8 weeks Reduced left ventricular interstitial and perivascular fibrosis Reduced TGF-β1 and phospho-Smad2/3 protein levels Castoldi et al. 2009, 2013
Type 1 and type 2 diabetic mice Mice, in vivo 1 mg/kg per day, up to 4 weeks Decreased renal fibrosis and protected renal function Reduced fibronectin, FSP-1, α-SMA proteins expression, and TGF-β/Smad pathway Nitta et al. 2016; Shibuya et al. 2005
Diabetes mellitus Mice, in vivo 0.5 mg/kg per day, 8 weeks Inhibited fibrosis and the EndMT in the heart and kidneys Inhibition of the EndMT associated with the restoration of FGFR1 and microRNA let-7, P-MAP4K4; inhibition of TGF-β/ Smad3 signaling Li et al. 2017; Nagai et al. 2014
Myocardial infarction Mice and rats, in vivo Ac-SDKP or Ac-SDDKDP at 0.8–1.6 mg/kg per day, 4–6 weeks Decreased cardiac rupture, inflammation, and fibrosis; improved angiogenesis and cardiac function Inhibited excessive inflammation, fibrosis, and ER stress; increased the expression of angiogenic genes and SERCA2a expression Ma et al. 2014; Nakagawa et al. 2018; Peng et al. 2013; Song et al. 2014; Wang et al. 2004a; Yang et al. 2004
Autoimmune myocarditis Rats, in vivo 0.8 mg/kg per day, 4 weeks Prevented both cardiac dysfunction, hypertrophy and fibrosis Inhibited innate and adaptive immune cell infiltration, inhibited expression of pro-inflammatory mediators such as cytokines (IL-1α, TNF-α, IL-2, IL-17), chemokines, adhesion molecules ICAM-1, L-selectin, and MMPs Nakagawa et al. 2012
Anti-glomerular basement membrane nephritis Rats, in vivo 1 mg/kg per day, 4 weeks Improved proteinuria and renal dysfunction, and inhibited glomerulosclerosis and interstitial fibrosis Suppressed gene and protein expression of fibronectin and macrophage infiltration; inhibited TGF-β1, Smad2 phosphorylation; and increased Smad7 expression Omata et al. 2006
Endothelial cells Mouse aortic endothelial cell line 0.01–10 nM Stimulated endothelial cell proliferation and migration and tube formation in a dose-dependent manner Possible mechanism linked to MMP-1 Liu et al. 2003; Wang et al. 2004a
Cardiac fibroblasts Human cells, in vitro 0.1–10 nM Inhibited TGF-β1-induced differentiation of fibroblasts into myofibroblasts Inhibited all the effects of TGF-β1, and inhibited ET-1-induced TGF-β1 production Peng et al. 2010
Cardiac fibroblasts Rats, in vitro 0.1–100 nM Inhibited collagenase expression and activation Inhibition of MMPs by Ac-SDKP was associated with increased TIMP-1 and TIMP-2 expressions Rhaleb et al. 2013
Cardiac fibroblasts Rats, in vitro 0.1–100 nM Inhibited ET-1-stimulated collagen production and cell proliferation Preserving SHP-2 activity and thereby preventing p44/42 MAPK activation Peng et al. 2012; Rhaleb et al. 2001a
Mesangial cells Human cells, in vitro 10 nM Inhibited cell proliferation Increased p53 and p27kip1 Kanasaki et al. 2006
Cancer cell lines Human and mouse cell lines, in vitro 5–100 μg/mL Regulated cell proliferation PI3KCA/Akt pathway mediates Ac-SDKP regulation of cell proliferation Hu et al. 2013

Note: CHOP, CCAAT-enhancer-binding protein homologous protein; C5–9, complement 5–9; DOCA, deoxycorticosterone-acetate; eIF2, eukaryotic initiation factor 2a; EndMT, endothelial-mesenchymal transition; ER, endoplasmic reticulum; ET-1, endothelin-1; FGFR1, fibroblast growth factor receptor 1; FSP-1, fibroblast-specific protein 1; Gal-3, galectin-3; HAE-A549, human alveolar epithelial cell line-A549; ICAM-1, intercellular adhesion molecule-1α; IL-1α, interleukin-1α; IL-2, interleukin-2; IL-17, interleukin-17; LOXL1, lysyl oxidase like1; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MCP-5, monocyte chemoattractant protein-5; MMPs, metalloproteinases; NF-κB, nuclear factor-κB; PAI-1, plasminogen activator inhibitor-1; PERK, protein kinase R ER kinase; PI3KCA/Akt, phosphatidylinositol-3 kinase-calcium/serinethreonine protein kinase; P-MAP4K4, mitogen activated protein kinase kinase kinase 4; p27kip1, member of the universal cyclin-dependent kinase inhibitor; p53, tumor protein (EC:2.7.1.37); RANTES, Regulated on Activation Normal T Cell Expressed and Secreted; RAS, renin–angiotensin system; SERCA2a, sarcoplasmic endoplasmic reticulum ATPase; α-SMA, α-smooth muscle actin; SHP, Src homology 2-containing protein tyrosine phosphatase-2; Smad, Suppressor of Mothers Against Decapentaplegic Miscellaneous; SRF, serum response factor; TGF-β1, transforming growth factor-β1; TIMP-1 and TIMP-2, metallopeptidase inhibitor-1, or −2; TNF-α, tumor necrosis factor-α.

Table 2.

Effects of thymosin β4 (Tβ4) in various diseases and experimental models.

Experimental model/
diseases
Species Dosage and duration Observed effects Mechanisms References

Developing early fetal heart Human NA T4 in the human heart is primarily localized to endothelial cells of the cardiac microvasculature and coronary vessels, as well as to the endothelial-like cells of the endocardium and to the epicardium NA Saunders et al. 2018
Cardiac-specific knockdown of Tβ4 Mice, in vivo Knockout mice Reduced coronary vasculogenesis and angiogenesis during embryogenesis and during cardiac injury Ac-SDKP release Smart et al. 2007
Global knockdown of Tβ4 Mice, in vivo Knockout mice Loss of endogenous Tβ4 had no effect on developing heart or cardiac structures and function in adult heart, but Tβ4 has antiinflammatory and antifibrotic role on heart and kidneys in Ang-II-induced hypertension Decreased renal and cardiac infiltration of CD68 macrophages, ICAM-1 in hypertensive animals Banerjee et al. 2012, 2013; Kumar et al. 2018
Global knockdown of Tβ4 Mice, in vivo Knockout mice Loss of endogenous Tβ4 accelerates glomerular disease Tμ4 knockdown in cultured podocytes also increased migration in a woundhealing assay, accompanied by F-actin rearrangement and increased RhoA activity Vasilopoulou et al. 2016
Liver injury induced by ethanol and LPS Mice, in vivo 1 mg/kg per day, 1 week Reduced liver oxidative stress, inflammation, and fibrosis Inhibited NF-κB; reduced TNF-α, IL-1β, and IL-6; suppressed the epigenetic repressor MeCP2; and increased PPARγ Shah et al. 2018a, 2018b
Unilateral ureteral obstruction Rats, in vivo 1 and 5 mg/kg per day, 2 weeks Decreased proteinuria and reduced renal injury Decreased TGF-β and α-SMA protein expression, increased E-cadherin Yuan et al. 2017
Acute stroke Aged rats, in vivo 12 mg/kg every 3 days, 2 weeks Reduced infarct volume but Tβ4 treatment did not improve functions, myelination, or gliosis Increased astrocytic gliosis Morris et al. 2017
Myocardial infarction Mice, in vivo 1.6 mg/kg per day, 6 weeks Prevented cardiac rupture, improved survival rate Reduced cardiac fibrosis and improved cardiac function Decreased cardiac apoptosis and inflammation, and increased cardiac capillary density Peng et al. 2014
Myocardial infarction Mice, in vivo 400 ng/μL intra-cardiac or 150 g/300 μL intraperitoneal Improved cardiac function and decreased scar tissue volume Increased ILK and Akt phosphorylation together with decreased cardiomyocyte apoptosis Bock-Marquette et al. 2004
Myocardial infarction Rats, in vivo 5.37 mg/kg immediately after surgery and every third day, up to 4 weeks Reduced infarct size, improved hemodynamic performances; no improvement on volume and ejection fractions No suggested mechanism Bao et al. 2013
Myocardial infarction with transfer of Tβ4-EPCs treated Rats, in vivo 0.05, 0.1, and 0.2 M to treat EPCs Promoted the survival and angiogenesis of transplanted endothelial progenitor cells in the infarcted myocardium Increased p-Akt expression in the endothelial cells Quan et al. 2017
Ang-II-induced hypertension Mice, in vivo 1.6 mg/kg per day, 6 weeks Tβ4 knockout mice had increased albuminuria and decreased nephrin expression in the kidney In Tβ4 knockout mice, Ang II reduced cardiac ejection fraction and increased cardiac hypertrophy and left ventricular dilatation, compared with wild type mice Exaggerated increased renal and cardiac infiltration of CD68 macrophages, ICAM-1, and total collagen content hypertensive Tβ4 in knockout versus wild type mice Kumar et al. 2018
Pulmonary hypertension Mice, in vivo 200 μg/200 μL PBS; Tβ4 every day for 3 days prior to MCT, followed by MCT daily for 1 week, then MCT twice weekly for 4 weeks Protected mice from MCT-induced pulmonary hypertension and right ventricular hypertrophy and fibrosis Selectively targets Notch3-Col 3 A-CTGF gene axis in preventing MCT-induced PH and RVH Wei et al. 2014
Patients with acute ST segment elevation myocardial infarction Human, in vitro then in vivo 1 μg/mL 24 hours before EPC injections Optimized EPC transplantation appeared to be feasible and safe NA Zhu et al. 2016
Murine colitis (model for Crohn’s disease Mice, in vivo Intracolonic AAV-Tβ4 (4 × 1010 viral genome) Protected from 2,4,6-trinitrobenzene sulfonic acid-induced colitis and suppressed proliferation of colonic epithelial cells Reduced inflammation; relieved oxidative stress; modulated TNF-Α, IL-1, and IL-10 Zheng et al. 2017
Cardiac fibroblasts Rats, in vitro 1 μg/mL Reduced H2O2-induced ROS levels and pro-fibrotic genes (CTGF, Col-1, and Col-3) Increased Cu/Zn SOD/catalase; reduced Bax/Bcl2 Kumar and Gupta 2011
Cultured HCEC, HCET, HCO597, COS-7, a7r5, PAC-1 and HEKa cells Human, in vitro; rats, in vitro Overexpression Inhibited injury-induced pro-inflammatory cytokine and chemokine production Inhibited TNF-Α-induced NF-B activation, IL-8 gene transcription, focal adhesion proteins PINCH-1 and ILK Qiu et al. 2011

Note: a7r5, rat artery smooth cell line; Ac-SDKP, N-acetyl-seryl-aspartyl-lysyl-proline; Ang II, angiotensin II; Bax/Bcl2, Bcl-2-associated X protein/B-cell lymphoma 2; CD68, cluster of differentiation 68; Col 3 A, collagen type III A; CTGF, connective tissue growth factor; Cu/Zn SOD, cupper/zinc superoxide dismutase; EPCs, endothelial progenitors cells; HCEC, adult human coronary epithelial cells; HCET, immortalized HCEC; HCO597, human corneal conjunctival epithelial cell line; HEKa, adult human epidermal keratinocytes; ICAM-1, intercellular adhesion molecule-1; ILK, integrin-linked kinase; IL-1α, interleukin-1α; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-8, interleukin-8; MCT, monocrotaline; MeCP2, methyl-CpG-binding protein 2; NA, not applicable; NF-B, nuclear factor-B; Notch3, neurogenic locus notch homolog protein 3; PAC-1, procaspase activating compound-1; PH, pulmonary hypertension; PINCH, focal adhesion protein; PPARγ, peroxisome proliferator-activated receptor-γ; RhoA, Ras homolog gene family, member A; RVH, right ventricular hypertrophy; α-SMA, α-smooth muscle actin; TGF-β1, transforming growth factor-β1; TNF-α, tumor necrosis factor-α.

Acknowledgements

The authors recognize the excellent editorial work by Emily Dobbs.

Footnotes

Conflict of interest

The authors declare that there is no conflict of interest associated with this work.

Contributor Information

Kamal M. Kassem, Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA Internal Medicine Department, University of Cincinnati Medical Center, Cincinnati, OH 45219, USA..

Sonal Vaid, Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA; Internal Medicine Department, St. Vincent Indianapolis Hospital, Indianapolis, IN 46260, USA..

Hongmei Peng, Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA..

Sarah Sarkar, Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA..

Nour-Eddine Rhaleb, Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA; Department of Physiology, Wayne State University, Detroit, MI 48201, USA..

References

  1. Anavekar NS, and Solomon SD 2005. Angiotensin II receptor blockade and ventricular remodelling. J. Renin Angiotensin Aldosterone Syst 6(1): 43–48. doi: 10.3317/jraas.2005.006. PMID:16088851. [DOI] [PubMed] [Google Scholar]
  2. Azizi M, Rousseau A, Ezan E, Guyene TT, Michelet S, Grognet JM, et al. 1996. Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline. J. Clin. Invest 97(3): 839–844. doi: 10.1172/JCI118484. PMID:8609242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Azizi M, Ezan E, Nicolet L, Grognet JM, and Ménard J. 1997. High plasma level of N-acetyl-seryl-aspartyl-lysyl-proline: a new marker of chronic angiotensin-converting enzyme inhibition. Hypertension, 30(5): 1015–1019. doi: 10.1161/01.HYP.30.5.1015. PMID:9369248. [DOI] [PubMed] [Google Scholar]
  4. Banerjee I, Zhang J, Moore-Morris T, Lange S, Shen T, Dalton ND, et al. 2012. Thymosin beta 4 is dispensable for murine cardiac development and function. Circ. Res 110(3): 456–464. doi: 10.1161/CIRCRESAHA.111.258616. PMID:22158707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Banerjee I, Moore Morris T, Evans SM, and Chen J. 2013. Thymosin beta4 is not required for embryonic viability or vascular development. Circ. Res 112(3): e25–e28. doi: 10.1161/CIRCRESAHA.111.300197. PMID:23371905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bao W, Ballard VL, Needle S, Hoang B, Lenhard SC, Tunstead JR, et al. 2013. Cardioprotection by systemic dosing of thymosin beta four following ischemic myocardial injury. Front. Pharmacol 4: 149. doi: 10.3389/fphar.2013.00149. PMID:24348421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bernstein KE, Shen XZ, Gonzalez-Villalobos RA, Billet S, Okwan-Duodu D, Ong FS, and Fuchs S. 2011. Different in vivo functions of the two catalytic domains of angiotensin-converting enzyme (ACE). Curr. Opin. Pharmacol 11(2): 105–111. doi: 10.1016/j.coph.2010.11.001. PMID:21130035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bock-Marquette I, Saxena A, White MD, DiMaio JM, and Srivastava D. 2004. Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature, 432(7016): 466–472. doi: 10.1038/nature03000. PMID:15565145. [DOI] [PubMed] [Google Scholar]
  9. Böhm M. 2007. Angiotensin receptor blockers versus angiotensin-converting enzyme inhibitors: where do we stand now? Am. J. Cardiol 100(3A): 38J–44J. doi: 10.1016/j.amjcard.2007.05.013. PMID:17666197. [DOI] [PubMed] [Google Scholar]
  10. Brown NJ, Kim KS, Chen YQ, Blevins LS, Nadeau JH, Meranze SG, and Vaughan DE 2000. Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production. J. Clin. Endocrinol. Metab 85(1): 336–344. doi: 10.1210/jcem.85.1.6305. PMID:10634408. [DOI] [PubMed] [Google Scholar]
  11. Carlström M, Wilcox CS, and Arendshorst WJ 2015. Renal autoregulation in health and disease. Physiol. Rev 95(2): 405–511. doi: 10.1152/physrev.00042.2012. PMID:25834230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Carretero OA, Yang XP, and Rhaleb N-E 2009. Kinins and cardiovascular disease In Renin angiotensin system and cardiovascular disease. Edited by DeMello WC and Frohlich ED. Humana Press; pp. 151–185. doi: 10.1007/978-1-60761-186-8_12. [DOI] [Google Scholar]
  13. Castoldi G, di Gioia CR, Bombardi C, Perego C, Perego L, Mancini M, et al. 2009. Prevention of myocardial fibrosis by N-acetyl-seryl-aspartyl-lysylproline in diabetic rats. Clin. Sci. (Lond.), 118(3): 211–220. doi: 10.1042/CS20090234. PMID:20310083. [DOI] [PubMed] [Google Scholar]
  14. Castoldi G, di Gioia CR, Bombardi C, Preziuso C, Leopizzi M, Maestroni S, et al. 2013. Renal antifibrotic effect of N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats. Am. J. Nephrol 37(1): 65–73. doi: 10.1159/000346116. PMID: 23327833. [DOI] [PubMed] [Google Scholar]
  15. Cavasin MA 2006. Therapeutic potential of thymosin-beta4 and its derivative N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) in cardiac healing after infarction. Am. J. Cardiovasc. Drugs, 6(5): 305–311. doi: 10.2165/00129784-200606050-00003. PMID:17083265. [DOI] [PubMed] [Google Scholar]
  16. Cavasin MA, Rhaleb N-E, Yang XP, and Carretero OA 2004. Prolyl oligopeptidase is involved in release of the antifibrotic peptide Ac-SDKP. Hypertension, 43(5): 1140–1145. doi: 10.1161/01.HYP.0000126172.01673.84. PMID: 15037553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Cavasin MA, Liao TD, Yang XP, Yang JJ, and Carretero OA 2007. Decreased endogenous levels of Ac-SDKP promote organ fibrosis. Hypertension, 50(1): 130–136. doi: 10.1161/HYPERTENSIONAHA.106.084103. PMID:17470726. [DOI] [PubMed] [Google Scholar]
  18. Chan GC, Yiu WH, Wu HJ, Wong DW, Lin M, Huang XR, et al. 2015. N-acetyl-seryl-aspartyl-lysyl-proline alleviates renal fibrosis induced by unilateral ureteric obstruction in BALB/C mice. Mediators Inflamm 2015: 283123. doi: 10.1155/2015/283123. PMID:26508815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Crockford D, Turjman N, Allan C, and Angel J. 2010. Thymosin beta4: structure, function, and biological properties supporting current and future clinical applications. Ann. N. Y. Acad. Sci 1194: 179–189. doi: 10.1111/j.1749-6632.2010.05492.x. PMID:20536467. [DOI] [PubMed] [Google Scholar]
  20. Danilov SM, Wade MS, Schwager SL, Douglas RG, Nesterovitch AB, Popova IA, et al. 2014. A novel angiotensin I-converting enzyme mutation (S333W) impairs N-domain enzymatic cleavage of the anti-fibrotic peptide, AcSDKP. PLoS One, 9(2): e88001. doi: 10.1371/journal.pone.0088001. PMID: 24505347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Forouhi NG, and Wareham NJ 2014. Epidemiology of diabetes. Medicine (Abingdon), 42(12): 698–702. doi: 10.1016/j.mpmed.2014.09.007. PMID:25568613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Fuchs S, Xiao HD, Cole JM, Adams JW, Frenzel K, Michaud A, et al. 2004. Role of the N-terminal catalytic domain of angiotensin-converting enzyme investigated by targeted inactivation in mice. J. Biol. Chem 279: 15946– 15953. doi: 10.1074/jbc.M400149200. PMID:14757757. [DOI] [PubMed] [Google Scholar]
  23. Gao XM, White DA, Dart AM, and Du XJ 2012. Post-infarct cardiac rupture: recent insights on pathogenesis and therapeutic interventions. Pharmacol. Ther 134(2): 156–179. doi: 10.1016/j.pharmthera.2011.12.010. PMID:22260952. [DOI] [PubMed] [Google Scholar]
  24. Gómez-Márquez J, Dosil M, Segade F, Bustelo XR, Pichel JG, Dominguez F, and Freire M. 1989. Thymosin-beta 4 gene. Preliminary characterization and expression in tissues, thymic cells, and lymphocytes. J. Immunol 143(8): 2740–2744. PMID:2677145. [PubMed] [Google Scholar]
  25. González GE, Rhaleb N-E, Nakagawa P, Liao TD, Liu Y, Leung P, et al. 2014. N-acetyl-seryl-aspartyl-lysyl-proline reduces cardiac collagen crosslinking and inflammation in angiotensin II-induced hypertensive rats. Clin. Sci. (Lond.), 126(1): 85–94. doi: 10.1042/CS20120619. PMID:23834332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Gupta RC, Wang MJ, Zhang KF, Sing-Gupta V, and Sabbah HN 2014. Thymosin β4 and its cleavage product Ac-SDKP are down-regulated in left ventricular myocardium of dogs with chronic heart failure. Circulation, 130 https://www.ahajournals.org/doi/abs/10.1161/circ.130.suppl_2.13767. [Google Scholar]
  27. Hannappel E. 2010. Thymosin beta4 and its posttranslational modifications. Ann. N. Y. Acad. Sci 1194: 27–35. doi: 10.1111/j.1749-6632.2010.05485.x. PMID: 20536447. [DOI] [PubMed] [Google Scholar]
  28. Hinkel R, El-Aouni C, Olson T, Horstkotte J, Mayer S, Müller S, et al. 2008. Thymosin beta4 is an essential paracrine factor of embryonic endothelial progenitor cell-mediated cardioprotection. Circulation, 117(17): 2232–2240. doi: 10.1161/CIRCULATIONAHA.107.758904. PMID:18427126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ho JH, Tseng KC, Ma WH, Chen KH, Lee OK, and Su Y. 2008. Thymosin beta-4 upregulates anti-oxidative enzymes and protects human cornea epithelial cells against oxidative damage. Br. J. Ophthalmol 92(7): 992–997. doi: 10.1136/bjo.2007.136747. PMID:18480304. [DOI] [PubMed] [Google Scholar]
  30. Hrenak J, Paulis L, and Simko F. 2015. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP): potential target molecule in research of heart, kidney and brain. Curr. Pharm. Des 21(35): 5135–5143. doi: 10.2174/1381612821666150909093927. PMID:26350537. [DOI] [PubMed] [Google Scholar]
  31. Hu P, Li B, Zhang W, Li Y, Li G, Jiang X, et al. 2013. AcSDKP regulates cell proliferation through the PI3KCA/Akt signaling pathway. PLoS One, 8(11): e79321. doi: 10.1371/journal.pone.0079321. PMID:24244481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Huff T, Rosorius O, Otto AM, Müller CS, Ballweber E, Hannappel E, and Mannherz HG 2004. Nuclear localisation of the G-actin sequestering peptide thymosin beta4. J. Cell Sci 117(Pt. 22): 5333–5341. doi: 10.1242/jcs.01404. PMID:15466884. [DOI] [PubMed] [Google Scholar]
  33. Junot C, Gonzales M-F, Ezan E, Cotton J, Vazeux G, Michaud A, et al. 2001. RPX 407, a selective inhibitor of the N-domain of angiotensin I-converting enzyme, blocks in vivo the degradation of hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro with no effect on angiotensin I hydrolysis. J. Pharmacol. Exp. Ther 297: 606–611. PMID:11303049. [PubMed] [Google Scholar]
  34. Kanasaki K, Haneda M, Sugimoto T, Shibuya K, Isono M, Isshiki K, et al. 2006. N-acetyl-seryl-aspartyl-lysyl-proline inhibits DNA synthesis in human mesangial cells via up-regulation of cell cycle modulators. Biochem. Biophys. Res. Commun 342: 758–765. doi: 10.1016/j.bbrc.2006.02.019. PMID:16497271. [DOI] [PubMed] [Google Scholar]
  35. Kumar N, Nakagawa P, Janic B, Romero CA, Worou ME, Monu SR, et al. 2016. The anti-inflammatory peptide Ac-SDKP is released from thymosinbeta4 by renal meprin-alpha and prolyl oligopeptidase. Am. J. Physiol. Renal Physiol 310(10): F1026–F1034. doi: 10.1152/ajprenal.00562.2015. PMID:26962108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Kumar N, Liao TD, Romero CA, Maheshwari M, Peterson EL, and Carretero OA 2018. Thymosin beta4 deficiency exacerbates renal and cardiac injury in angiotensin-II-induced hypertension. Hypertension, 71(6): 1133–1142. doi: 10.1161/HYPERTENSIONAHA.118.10952. PMID:29632102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Kumar S, and Gupta S. 2011. Thymosin beta 4 prevents oxidative stress by targeting antioxidant and anti-apoptotic genes in cardiac fibroblasts. PLoS One, 6(10): e26912. doi: 10.1371/journal.pone.0026912. PMID:22046407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Leuschner F, Panizzi P,Chico-Calero I, Lee WW, Ueno T, Cortez-Retamozo V, et al. 2010. Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction. Circ. Res 107(11): 1364–1373. doi: 10.1161/CIRCRESAHA.110.227454. PMID: 20930148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Li J, Shi S, Srivastava SP, Kitada M, Nagai T, Nitta K, et al. 2017. FGFR1 is critical for the anti-endothelial mesenchymal transition effect of N-acetylseryl-aspartyl-lysyl-proline via induction of the MAP4K4 pathway. Cell Death Dis 8(8): e2965. doi: 10.1038/cddis.2017.353. PMID:28771231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Li P, Xiao HD, Xu J, Ong FS, Kwon M, Roman J, et al. 2010. Angiotensinconverting enzyme N-terminal inactivation alleviates bleomycin-induced lung injury. Am. J. Pathol 177(3): 1113–1121. doi: 10.2353/ajpath.2010.081127. PMID:20651228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Liao TD, Yang XP, D’Ambrosio M, Zhang Y, Rhaleb N-E, and Carretero OA 2010. N-acetyl-seryl-aspartyl-lysyl-proline attenuates renal injury and dysfunction in hypertensive rats with reduced renal mass: Council for High Blood Pressure Research. Hypertension, 55(2): 459–467. doi: 10.1161/HYPERTENSIONAHA.109.144568. PMID:20026760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Liao TD, Nakagawa P, Janic B, D’Ambrosio M, Worou ME, Peterson EL, et al. 2015. N-acetyl-seryl-aspartyl-lysyl-proline: mechanisms of renal protection in mouse model of systemic lupus erythematosus. Am. J. Physiol. Renal Physiol 308(10): F1146–F1154. doi: 10.1152/ajprenal.00039.2015. PMID:25740596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Lin CX, Rhaleb N-E, Yang XP, Liao TD, D’Ambrosio MA, and Carretero OA 2008. Prevention of aortic fibrosis by N-acetyl-seryl-aspartyllysyl-proline in angiotensin II-induced hypertension. Am. J. Physiol. Heart Circ. Physiol 295(3): H1253–H1261. doi: 10.1152/ajpheart.00481.2008. PMID: 18641275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Liu JM, Lawrence F, Kovacevic M, Bignon J, Papadimitriou E, Lallemand JY, et al. 2003. The tetrapeptide AcSDKP, an inhibitor of primitive hematopoietic cell proliferation, induces angiogenesis in vitro and in vivo. Blood, 101(8): 3014–3020. doi: 10.1182/blood-2002-07-2315. PMID:12480715. [DOI] [PubMed] [Google Scholar]
  45. Liu YH, Yang XP, Sharov VG, Nass O, Sabbah HN, Peterson E, and Carretero OA 1997. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. J. Clin. Invest 99(8): 1926–1935. doi: 10.1172/JCI119360. PMID:9109437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Liu YH, Xu J, Yang XP, Yang F, Shesely E, and Carretero OA 2002. Effect of ACE inhibitors and angiotensin II type 1 receptor antagonists on endothelial NO synthase knockout mice with heart failure. Hypertension, 39(2 Pt. 2): 375–381. doi: 10.1161/hy02t2.102796. PMID:11882576. [DOI] [PubMed] [Google Scholar]
  47. Liu YH, Wang D, Rhaleb NE, Yang XP, Xu J, Sankey SS, et al. 2005. Inhibition of p38 mitogen-activated protein kinase protects the heart against cardiac remodeling in mice with heart failure resulting from myocardial infarction. J. Card. Fail 11(1): 74–81. doi: 10.1016/j.cardfail.2004.04.004. PMID: 15704068. [DOI] [PubMed] [Google Scholar]
  48. Liu YH, D’Ambrosio M, Liao TD, Peng H, Rhaleb N-E, Sharma U, et al. 2009. N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin.Am.J.Physiol.HeartCirc.Physiol 296(2):H404–H412.doi: 10.1152/ajpheart.00747.2008. PMID:19098114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Ma LJ, and Fogo AB 2009. PAI-1 and kidney fibrosis. Front. Biosci. (Landmark Ed.), 14: 2028–2041. PMID:19273183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Ma X, Yuan Y, Zhang Z, Zhang Y, and Li M. 2014. An analog of Ac-SDKP improves heart functions after myocardial infarction by suppressing alternative activation (M2) of macrophages. Int. J. Cardiol 175(2): 376–378. doi: 10.1016/j.ijcard.2014.05.016. PMID:24874903. [DOI] [PubMed] [Google Scholar]
  51. Marcy TR, and Ripley TL 2006. Aldosterone antagonists in the treatment of heart failure. Am. J. Health Syst. Pharm 63(1): 49–58. doi: 10.2146/ajhp050041. PMID:16373465. [DOI] [PubMed] [Google Scholar]
  52. Mora CA, Baumann CA, Paino JE, Goldstein AL, and Badamchian M. 1997. Biodistribution of synthetic thymosin beta4 in the serum, urine, and major organs of mice. Int. J. ImmunoPharmacol 19(1): 1–8. doi: 10.1016/S0192-0561(97)00005-2. PMID:9226473. [DOI] [PubMed] [Google Scholar]
  53. Morris DC, Cheung WL, Loi R, Zhang T, Lu M, Zhang ZG, and Chopp M. 2017. Thymosin beta4 for the treatment of acute stroke in aged rats. Neurosci. Lett 659: 7–13. doi: 10.1016/j.neulet.2017.08.064. PMID:28864242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Nagai T, Kanasaki M, Srivastava SP, Nakamura Y, Ishigaki Y, Kitada M, et al. 2014. N-acetyl-seryl-aspartyl-lysyl-proline inhibits diabetes-associated kidney fibrosis and endothelial-mesenchymal transition. Biomed. Res. Int 2014: 696475. doi: 10.1155/2014/696475. PMID:24783220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Nakagawa P, Liu Y, Liao TD, Chen X, González GE, Bobbitt KR, et al. 2012. Treatment with N-acetyl-seryl-aspartyl-lysyl-proline prevents experimental autoimmune myocarditis in rats. Am. J. Physiol. Heart Circ. Physiol 303(9): H1114–H1127. doi: 10.1152/ajpheart.00300.2011. PMID:22923621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Nakagawa P, Masjoan-Juncos JX, Basha H, Janic B, Worou ME, Liao TD, et al. 2017. Effects of N-acetyl-seryl-asparyl-lysyl-proline on blood pressure, renal damage, and mortality in systemic lupus erythematosus. Physiol. Rep 5(2): e13084. doi: 10.14814/phy2.13084. PMID:28126732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Nakagawa P, Romero CA, Jiang X, D’Ambrosio M, Bordcoch G, Peterson EL, et al. 2018. Ac-SDKP decreases mortality and cardiac rupture after acute myocardial infarction. PLoS One, 13(1): e0190300. doi: 10.1371/journal.pone.0190300. PMID:29364896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Nathan CF 1987. Secretory products of macrophages. J. Clin. Invest 79: 319–326. doi: 10.1172/JCI112815. PMID:3543052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Nitta K, Shi S, Nagai T, Kanasaki M, Kitada M, Srivastava SP, et al. 2016. Oral administration of N-acetyl-seryl-aspartyl-lysyl-proline ameliorates kidney disease in both type 1 and type 2 diabetic mice via a therapeutic regimen. Biomed. Res. Int 2016: 9172157. doi: 10.1155/2016/9172157. PMID:27088094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Omata M, Taniguchi H, Koya D, Kanasaki K, Sho R, Kato Y, et al. 2006. N-acetyl-seryl-aspartyl-lysyl-proline ameliorates the progression of renal dysfunction and fibrosis in WKY rats with established anti-glomerular basement membrane nephritis. J. Am. Soc. Nephrol 17(3): 674–685. doi: 10.1681/ASN.2005040385. PMID:16452498. [DOI] [PubMed] [Google Scholar]
  61. Peng H, Carretero OA, Raij L, Yang F, Kapke A, and Rhaleb N-E 2001. Antifibrotic effects of N-acetyl-seryl-aspartyl-lysyl-proline on the heart and kidney in aldosterone-salt hypertensive rats. Hypertension, 37(2 Pt. 2): 794–800. doi: 10.1161/01.HYP.37.2.794. PMID:11230375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Peng H, Carretero OA, Vuljaj N, Liao TD, Motivala A, Peterson EL, and Rhaleb N-E 2005. Angiotensin-converting enzyme inhibitors: a new mechanism of action. Circulation, 112(16): 2436–2445. doi: 10.1161/CIRCULATIONAHA.104.528695. PMID:16216963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Peng H, Carretero OA, Liao TD, Peterson EL, and Rhaleb N-E 2007. Role of N-acetyl-seryl-aspartyl-lysyl-proline in the antifibrotic and anti-inflammatory effects of the angiotensin-converting enzyme inhibitor captopril in hypertension. Hypertension, 49(3): 695–703. doi: 10.1161/01.HYP.0000258406.66954.4f. PMID:17283252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Peng H, Carretero OA, Peterson EL, and Rhaleb N-E 2010. Ac-SDKP inhibits transforming growth factor-beta1-induced differentiation of human cardiac fibroblasts into myofibroblasts. Am. J. Physiol. Heart Circ. Physiol 298(5): H1357–H1364. doi: 10.1152/ajpheart.00464.2009. PMID:20154264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Peng H, Carretero OA, Peterson EL, Yang XP, Santra K, and Rhaleb NE 2012. N-acetyl-seryl-aspartyl-lysyl-proline inhibits ET-1-induced collagen production by preserving Src homology 2-containing protein tyrosine phosphatase-2 activity in cardiac fibroblasts. Pflugers Arch 464(4): 415–423. doi: 10.1007/s00424-012-1150-7. PMID:22968858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Peng H, Xu J, Yang X-P, Dai X, Peterson E, Carretero OA, and Rhaleb N-E 2013. Ac-SDKP protects the heart from post-myocardial infarction remodeling and dysfunction in mice. Hypertension, 62(1): A99. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Peng H, Xu J, Yang XP, Dai X, Peterson EL, Carretero OA, and Rhaleb NE 2014. Thymosin-beta4 prevents cardiac rupture and improves cardiac function in mice with myocardial infarction. Am. J. Physiol. Heart Circ. Physiol 307(5): H741–H751. doi: 10.1152/ajpheart.00129.2014. PMID: 25015963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Peng H, Xu J, Yang XP, Kassem K, Rhaleb I, Peterson E, and Rhaleb NE 2019. AC-SDKP treatment protects heart against excessive myocardial injury and heart failure in mice. Can. J. Physiol. Pharmacol In press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Piccoli GB, Grassi G, Cabiddu G, Nazha M, Roggero S, Capizzi I, et al. 2015. Diabetic kidney disease: a syndrome rather than a single disease. Rev. Diabet. Stud 12(1–2): 87–109. doi: 10.1900/RDS.2015.12.87. PMID:26676663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Pokharel S, Rasoul S, Roks AJ, van Leeuwen RE, van Luyn MJ, Deelman LE, et al. 2002. N-acetyl-Ser-Asp-Lys-Pro inhibits phosphorylation of Smad2 in cardiac fibroblasts. Hypertension, 40(2): 155–161. doi: 10.1161/01.HYP.0000025880.56816.FA. PMID:12154106. [DOI] [PubMed] [Google Scholar]
  71. Pokharel S, van Geel PP, Sharma UC, Cleutjens JP, Bohnemeier H, Tian XL, et al. 2004. Increased myocardial collagen content in transgenic rats overexpressing cardiac angiotensin-converting enzyme is related to enhanced breakdown of N-acetyl-Ser-Asp-Lys-Pro and increased phosphorylation of Smad2/3. Circulation, 110(19): 3129–3135. doi: 10.1161/01.CIR.0000147180.87553.79. PMID:15520311. [DOI] [PubMed] [Google Scholar]
  72. Polgár L. 2002. The prolyl oligopeptidase family. Cell. Mol. Life Sci 59(2): 349–362. doi: 10.1007/s00018-002-8427-5. PMID:11915948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Qiu P, Wheater MK, Qiu Y, and Sosne G. 2011. Thymosin beta4 inhibits TNF-Αalpha-induced NF-kappaB activation, IL-8 expression, and the sensitizing effects by its partners PINCH-1 and ILK. FASEB J. 25(6): 1815–1826. doi: 10.1096/fj.10-167940. PMID:21343177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Quan Z, Wang QL, Zhou P, Wang GD, Tan YZ, and Wang HJ 2017. Thymosin beta4 promotes the survival and angiogenesis of transplanted endothelial progenitor cells in the infarcted myocardium. Int. J. Mol. Med 39(6): 1347–1356. doi: 10.3892/ijmm.2017.2950. PMID:28440414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Rhaleb N-E, Peng H, Harding P, Tayeh M, LaPointe MC, and Carretero OA 2001a. Effect of N-acetyl-seryl-aspartyl-lysyl-proline on DNA and collagen synthesis in rat cardiac fibroblasts. Hypertension, 37(3): 827–832. doi: 10.1161/01.HYP.37.3.827. PMID:11244003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Rhaleb N-E, Peng H, Yang XP, Liu YH, Mehta D, Ezan E, and Carretero OA 2001b. Long-term effect of N-acetyl-seryl-aspartyl-lysyl-proline on left ventricular collagen deposition in rats with 2-kidney, 1-clip hypertension. Circulation, 103(25): 3136–3141. doi: 10.1161/01.CIR.103.25.3136. PMID: 11425781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Rhaleb N-E, Pokharel S, Sharma U, and Carretero OA 2011. Renal protective effects of N-acetyl-Ser-Asp-Lys-Pro in deoxycorticosterone acetate-salt hypertensive mice. J. Hypertens 29(2): 330–338. doi: 10.1097/HJH.0b013e32834103ee. PMID:21052020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Rhaleb N-E, Pokharel S, Sharma UC, Peng H, Peterson E, Harding P, et al. 2013. N-acetyl-Ser-Asp-Lys-Pro inhibits interleukin-1beta-mediated matrix metalloproteinase activation in cardiac fibroblasts. Pflugers Arch 465(10): 1487–1495. doi: 10.1007/s00424-013-1262-8. PMID:23652767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Rodríguez-Lara SQ, García-Benavides L, and Miranda-Díaz AG 2018. The renin-angiotensin-aldosterone system as a therapeutic target in late injury caused by ischemia-reperfusion. Int. J. Endocrinol 2018: 3614303. doi: 10.1155/2018/3614303. PMID:29849615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Romero CA, Vaid S, Kumar N, Liao TD, and Carretero OA 2017. Cardioprotective peptide Ac-SDKP is highly concentrated in lymph nodes. Hypertension, 70(1): AP289. [Google Scholar]
  81. Rosendorff C, Lackland DT, Allison M, Aronow WS, Black HR, Blumenthal RS, et al. 2015. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. Circulation, 131(19): e435–e470. doi: 10.1161/CIR.0000000000000207. PMID:25829340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Roth LW, Bormann P, Wiederkehr C, and Reinhard E. 1999. Beta-thymosin, a modulator of the actin cytoskeleton is increased in regenerating retinal ganglion cells. Eur. J. NeuroSci 11(10): 3488–3498. doi: 10.1046/j.1460-9568.1999.00715.x. PMID:10564357. [DOI] [PubMed] [Google Scholar]
  83. Russell SM, Keegan AD, Harada N, Nakamura Y, Noguchi M, Leland P, et al. 1993. Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor. Science, 262(5141): 1880–1883. doi: 10.1126/science.8266078. PMID:8266078. [DOI] [PubMed] [Google Scholar]
  84. Sabbah HN, Gupta RC, and Singh-Gupta V. 2015. Thymosin beta4 and its cleavage product Ac-SDKP are down-regulated in left ventricular myocardium of patients with advanced heart failure. J. Heart Lung Transplant. 34(4): S89. doi: 10.1016/j.healun.2015.01.238. [DOI] [Google Scholar]
  85. Sato A, Saruta T, and Funder JW 2006. Combination therapy with aldosterone blockade and renin-angiotensin inhibitors confers organ protection. Hypertens. Res 29(4): 211–216. doi: 10.1291/hypres.29.211. PMID:16778327. [DOI] [PubMed] [Google Scholar]
  86. Saunders V, Dewing JM, Sanchez-Elsner T, and Wilson DI 2018. Expression and localisation of thymosin beta-4 in the developing human early fetal heart. PLoS One, 13(11): e0207248. doi: 10.1371/journal.pone.0207248. PMID: 30412598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Shah R, Reyes-Gordillo K, Cheng Y, Varatharajalu R, Ibrahim J, and Lakshman MR 2018a. Thymosin beta4 prevents oxidative stress, inflammation, and fibrosis in ethanol- and LPS-induced liver injury in mice. Oxid. Med. Cell. Longev 2018: 9630175. doi: 10.1155/2018/9630175. PMID:30116499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Shah R, Reyes-Gordillo K, and Rojkind M. 2018b. Thymosin beta4 inhibits PDGF-BB induced activation, proliferation, and migration of human hepatic stellate cells via its actin-binding domain. Expert Opin. Biol. Ther 18(Suppl. 1): 177–184. doi: 10.1080/14712598.2018.1478961. PMID:30063851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Shibuya K, Kanasaki K, Isono M, Sato H, Omata M, Sugimoto T, et al. 2005. N-acetyl-seryl-aspartyl-lysyl-proline prevents renal insufficiency and mesangial matrix expansion in diabetic db/db mice. Diabetes, 54: 838–845. doi: 10.2337/diabetes.54.3.838. PMID:15734863. [DOI] [PubMed] [Google Scholar]
  90. Shin SH, Lee S, Bae JS, Jee JG, Cha HJ, and Lee YM 2014. Thymosin beta4 regulates cardiac valve formation via endothelial-mesenchymal transformation in zebrafish embryos. Mol. Cells, 37(4): 330–336. doi: 10.14348/molcells.2014.0003. PMID:24732964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Smart N, Risebro CA, Melville AA, Moses K, Schwartz RJ, Chien KR, and Riley PR 2007. Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization. Nature, 445(7124): 177–182. doi: 10.1038/nature05383. PMID:17108969. [DOI] [PubMed] [Google Scholar]
  92. Song M, Jang H, Lee J, Kim JH, Kim SH, Sun K, and Park Y. 2014. Regeneration of chronic myocardial infarction by injectable hydrogels containing stem cell homing factor SDF-1 and angiogenic peptide Ac-SDKP. Biomaterials, 35(8): 2436–2445. doi: 10.1016/j.biomaterials.2013.12.011. PMID:24378015. [DOI] [PubMed] [Google Scholar]
  93. Strauss MH, and Hall AS 2018. The divergent cardiovascular effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers in adult patients with type 2 diabetes mellitus. Can. J. Diabetes, 42(2): 124–129. doi: 10.1016/j.jcjd.2017.09.011. PMID:29277343. [DOI] [PubMed] [Google Scholar]
  94. Tan H, Zhao J, Wang S, Zhang L, Wang H, Huang B, et al. 2012. Ac-SDKP ameliorates the progression of lupus nephritis in MRL/lpr mice. Int. ImmunoPharmacol 14(4): 401–409. doi: 10.1016/j.intimp.2012.07.023. PMID:22922317. [DOI] [PubMed] [Google Scholar]
  95. Tang SC, Leung JC, Chan LY, Eddy AA, and Lai KN 2008. Angiotensin converting enzyme inhibitor but not angiotensin receptor blockade or statin ameliorates murine adriamycin nephropathy. Kidney Int 73(3): 288–299. doi: 10.1038/sj.ki.5002674. PMID:18033243. [DOI] [PubMed] [Google Scholar]
  96. van der Meer IM, Cravedi P, and Remuzzi G. 2010. The role of renin angiotensin system inhibition in kidney repair. Fibrogenesis Tissue Repair, 3: 7. doi: 10.1186/1755-1536-3-7. PMID:20441574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Vasilopoulou E, Kolatsi-Joannou M, Lindenmeyer MT, White KE, Robson MG, Cohen CD, et al. 2016. Loss of endogenous thymosin beta4 accelerates glomerular disease. Kidney Int 90(5): 1056–1070. doi: 10.1016/j.kint.2016.06.032. PMID:27575556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Wang D, Carretero OA, Yang XY, Rhaleb N-E, Liu YH, Liao TD, and Yang X-P 2004a. N-acetyl-seryl-aspartyl-lysyl-proline stimulates angiogenesis in vitro and in vivo. Am. J. Physiol. Heart Circ. Physiol 287(5): H2099– H2105. doi: 10.1152/ajpheart.00592.2004. PMID:15256375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Wang D, Liu YH, Yang XP, Rhaleb N-E, Xu J, Peterson E, et al. 2004b. Role of a selective aldosterone blocker in mice with chronic heart failure. J. Card. Fail 10: 67–73. doi: 10.1016/S1071-9164(03)00578-5. PMID:14966777. [DOI] [PubMed] [Google Scholar]
  100. Wang L, Chopp M, Jia L, Lu X, Szalad A, Zhang Y, et al. 2015. Therapeutic benefit of extended thymosin beta4 treatment is independent of blood glucose level in mice with diabetic peripheral neuropathy. J. Diabetes Res 2015: 173656. doi: 10.1155/2015/173656. PMID:25945352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Wei C, Kim IK, Li L, Wu L, and Gupta S. 2014. Thymosin beta 4 protects mice from monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy. PLoS One, 9(11): e110598. doi: 10.1371/journal.pone.0110598. PMID:25412097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Worou ME, Liao TD, D’Ambrosio M, Nakagawa P, Janic B, Peterson EL, et al. 2015. Renal protective effect of N-acetyl-seryl-aspartyl-lysyl-proline in dahl saltsensitive rats. Hypertension, 66(4): 816–822. doi: 10.1161/HYPERTENSIONAHA.115.05970. PMID:26324505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Xu H, Yang F, Sun Y, Yuan Y, Cheng H, Wei Z, et al. 2012. A new antifibrotic target of Ac-SDKP: inhibition of myofibroblast differentiation in rat lung with silicosis. PLoS One, 7(7): e40301. doi: 10.1371/journal.pone.0040301. PMID:22802960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Xu J, Carretero OA, Liu YH, Shesely EG, Yang F, Kapke A, and Yang XP 2002. Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension, 40(3): 244–250. doi: 10.1161/01.HYP.0000029095.23198.AD. PMID:12215461. [DOI] [PubMed] [Google Scholar]
  105. Xu J, Carretero OA, Liu YH, Yang F, Shesely EG, Oja-Tebbe N, and Yang XP 2004. Dual inhibition of ACE and NEP provides greater cardioprotection in mice with heart failure.J.Card.Fail 10:83–89.doi: 10.1016/j.cardfail.2003.08.008. PMID:14966779. [DOI] [PubMed] [Google Scholar]
  106. Yang F, Yang XP, Liu YH, Xu J, Cingolani O, Rhaleb N-E, and Carretero OA 2004. Ac-SDKP reverses inflammation and fibrosis in rats with heart failure after myocardial infarction. Hypertension, 43(2): 229–236. doi: 10.1161/01.HYP.0000107777.91185.89. PMID:14691195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Yang XP, Liu YH, Mehta D, Cavasin MA, Shesely E, Xu J, et al. 2001. Diminished cardioprotective response to inhibition of angiotensin-converting enzyme and angiotensin II type 1 receptor in B(2) kinin receptor gene knockout mice. Circ. Res 88(10): 1072–1079. doi: 10.1161/hh1001.090759. PMID:11375278. [DOI] [PubMed] [Google Scholar]
  108. Yuan J, Shen Y, Yang X, Xie Y, Lin X, Zeng W, et al. 2017. Thymosin beta4 alleviates renal fibrosis and tubular cell apoptosis through TGF-beta pathway inhibition in UUO rat models. BMC Nephrol 18: 314. doi: 10.1186/s12882-017-0708-1. PMID:29047363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Zhang L, Chopp M, Teng H, Ding G, Jiang Q, Yang XP, et al. 2014. Combination treatment with N-acetyl-seryl-aspartyl-lysyl-proline and tissue plasminogen activator provides potent neuroprotection in rats after stroke. Stroke, 45(4): 1108–1114. doi: 10.1161/STROKEAHA.113.004399. PMID:24549864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Zhang L, Xu D, Li Q, Yang Y, Xu H, Wei Z, et al. 2018. N-acetyl-serylaspartyl-lysyl-proline (Ac-SDKP) attenuates silicotic fibrosis by suppressing apoptosis of alveolar type II epithelial cells via mediation of endoplasmic reticulum stress. Toxicol. Appl. Pharmacol 350: 1–10. doi: 10.1016/j.taap.2018.04.025. PMID:29684394. [DOI] [PubMed] [Google Scholar]
  111. Zhang Y, Zhang ZG, Chopp M, Meng Y, Zhang L, Mahmood A, and Xiong Y. 2017. Treatment of traumatic brain injury in rats with N-acetylseryl-aspartyl-lysyl-proline. J. Neurosurg 126(3): 782–795. doi: 10.3171/2016.3.JNS152699. PMID:28245754. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Zheng XY, Lv YF, Li S, Li Q, Zhang QN, Zhang XT, and Hao ZM 2017. Recombinant adeno-associated virus carrying thymosin beta4 suppresses experimental colitis in mice. World J. Gastroenterol 23(2): 242–255. doi: 10.3748/wjg.v23.i2.242. PMID:28127198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Zhu J, Song J, Yu L, Zheng H, Zhou B, Weng S, and Fu G. 2016. Safety and efficacy of autologous thymosin beta4 pre-treated endothelial progenitor cell transplantation in patients with acute ST segment elevation myocardial infarction: a pilot study. Cytotherapy, 18(8): 1037–1042. doi: 10.1016/j.jcyt.2016.05.006. PMID:27288307. [DOI] [PubMed] [Google Scholar]
  114. Zhu L, Carretero OA, Xu J, Wang L, Harding P, Rhaleb NE, et al. 2012. Angiotensin II type 2 receptor-stimulated activation of plasma prekallikrein and bradykinin release: role of SHP-1. Am. J. Physiol. Heart. Circ. Physiol 302(12): H2553–H2559. doi: 10.1152/ajpheart.01157.2011. PMID:22523247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Zuo Y, Chun B, Potthoff SA, Kazi N, Brolin TJ, Orhan D, et al. 2013. Thymosin beta4 and its degradation product, Ac-SDKP, are novel reparative factors in renal fibrosis. Kidney Int 84(6): 1166–1175. doi: 10.1038/ki.2013.209. PMID:23739235. [DOI] [PMC free article] [PubMed] [Google Scholar]

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