Regulation of Cardiovascular Health and Disease by Visceral Adipose Tissue-Derived Metabolic Hormones

Abstract

Visceral adipose tissue (VAT) is a metabolic organ known to regulate fat mass, and glucose and nutrient homeostasis. VAT is an active endocrine gland that synthesizes and secretes numerous bioactive mediators called “adipocytokines/adipokines” into systemic circulation. These adipocytokines act on organs of metabolic importance like the liver and skeletal muscle. Multiple preclinical and in vitro studies showed strong evidence of the roles of adipocytokines in the regulation of metabolic disorders like diabetes, obesity and insulin resistance. Adipocytokines, such as adiponectin and omentin, are anti-inflammatory and have been shown to prevent atherogenesis by increasing nitric oxide (NO) production by the endothelium, suppressing endothelium-derived inflammation and decreasing foam cell formation. By inhibiting differentiation of vascular smooth muscle cells (VSMC) into osteoblasts, adiponectin and omentin prevent vascular calcification. On the other hand, adipocytokines like leptin and resistin induce inflammation and endothelial dysfunction that leads to vasoconstriction. By promoting VSMC migration and proliferation, extracellular matrix degradation and inflammatory polarization of macrophages, leptin and resistin increase the risk of atherosclerotic plaque vulnerability and rupture. Additionally, the plasma concentrations of these adipocytokines alter in ageing, rendering older humans vulnerable to cardiovascular disease. The disturbances in the normal physiological concentrations of these adipocytokines secreted by VAT under pathological conditions impede the normal functions of various organs and affect cardiovascular health. These adipokines could be used for both diagnostic and therapeutic purposes in cardiovascular disease.

Graphical Abstract

Schematic illustration describing the potential beneficial and harmful effects of adipose tissue-derived hormones called “adipocytokines” on cardiovascular health and disease: Adiponectin and omentin, the anti-inflammatory adipocytokines, are beneficial for cardiovascular health. In endothelial cells, these adipocytokines, by activating endothelial nitric oxide synthase (eNOS), enhance endothelial derived nitric oxide (NO) production, and attenuate extravasation of monocytes into sub-endothelial space. These adipocytokines prevent differentiation of vascular smooth muscle cells (VSMC) into osteoblasts, deposition of inorganic phosphate crystals and subsequent progression of vascular calcifications. In macrophages, these adipocytokines promote exporting of lipid moieties and cholesterol out of macrophages and prevent foam cell formation. On the other hand, the pro-inflammatory adipocytokines, such as resistin and leptin, deteriorate cardiovascular health. Stimulation of endothelial cells by resistin and leptin leads to cellular senescence, inflammation, ROS generation, and subsequent vasoconstriction. These pro-inflammatory adipocytokines enhance abnormal cell cycle progression and proliferation of VSMC, propagating atherosclerosis. Furthermore, in atherosclerotic lesions, resistin and leptin augment MMP production by VSMC and encourage their migration. Resistin and leptin heighten lipid uptake, foam cell accumulation and atherosclerotic plaque burden.

Introduction:

Compelling evidence from a multitude of clinical, animal and cellular studies implicate that traditional cardiovascular risk factors like body mass index (BMI), hyperlipidemia, hypertension, type 2 diabetes and insulin resistance (IR) are associated with the accumulation of visceral adipose tissue (VAT) and subcutaneous fat (Lee et al., 2016; Gonzalez et al., 2017). Excessive VAT mass is more pathogenic than subcutaneous fat build-up because VAT dysfunction is closely linked to cardiometabolic abnormalities (Gonzalez et al., 2017). Besides regulating fat mass and nutrient homeostasis, VAT is an active endocrine organ that synthesizes and secretes a large number of bioactive mediators called “adipocytokines / adipokines” (Nishimura, Manabe, and Nagai 2009; Maurizi et al., 2018). These adipokines signal to organs of metabolic importance, including liver, skeletal muscle, and the immune system, and modulate tissue homeostasis, lipid and glucose metabolism, and inflammation (Samaras et al., 2010; Dutheil et al., 2018). Adipokines are produced and secreted by adipocytes and stromal cells within VAT, including fibroblasts, macrophages and T‐cells (Oikonomou and Antoniades 2019). While adiponectin and omentin are primarily anti-inflammatory and exert cardioprotective effects (Recinella et al., 2020; Greulich et al., 2013), leptin and resistin are primarily pro-inflammatory (Vendrell et al., 2004) and have adverse cardiovascular effects. Therefore, adipocytokines have recently emerged as potential biomarkers for the assessment of cardiovascular health and risk. In this review, effects of these adipokines on vascular and immune cells like endothelial cells, smooth muscle cells, macrophages and cardiomyocytes are discussed in detail, along with their clinical implications and therapeutic potentials.

1. Adiponectin:

Adiponectin, the most abundant adipokine, is a critical messenger that mediates crosstalk among adipose tissue, liver and muscle (Wang and Scherer 2016). Circulating levels of adiponectin are approximately 2–6 orders of magnitude greater than other adipocytokines, and inversely corelate with body fat mass (Swarbrick and Havel 2008). Adiponectin exerts its effects primarily via two receptors - adiponectin receptor-1 and -2 (AdipoR1/2). Adiponectin promotes insulin sensitization by improving fatty acid oxidation in the liver and skeletal muscle, and suppressing hepatic gluconeogenesis and oxidative stress (Iwabu et al., 2015). Experimental studies in vascular endothelial cells (EC), endothelial progenitor cells (EPC), smooth muscle cells (SMC), macrophages and cardiomyocytes in vitro, and animal models have documented the cardioprotective actions of adiponectin (Ouchi, Shibata, and Walsh 2006). Comprehensive experimental evidence demonstrated that adiponectin mediates several cardioprotective effects such as protection against atherosclerosis, inflammation and cardiometabolic disorders (Ouchi and Walsh 2007; Shimada, Miyazaki, and Daida 2004). Data from both human and animal studies demonstrated that adiponectin is an important component of the adipo‐vascular axis that mediates the cross‐talk between adipose tissue and vasculature (Li et al., 2011). Figure 1 summarizes the potential benefits of adiponectin in various types of cells present in the vasculature. Adiponectin exerts pleotropic effects on cardiovascular health primarily by maintaining endothelial function, attenuating vascular calcifications and inflammation, and preventing foam cells accumulation and cardiac fibrosis.

Figure 1:

Cardiovascular protective effects of the anti-inflammatory adipocytokines.

1A. Adiponectin improves vascular function by enhancing eNOS signaling and endothelial function:

Adiponectin improves endothelial function by increasing phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and nitric oxide (NO) levels (Deng et al., 2010). NO enhances vasodilation, lessens platelet aggregation, monocyte adhesion and SMC proliferation in blood vessels, and protects arteries against atherosclerotic plaque formation (Infante, Costa, and Napoli 2021; Kuhlencordt et al., 2004; Radomski, Palmer, and Moncada 1987; Ignarro et al., 2001). Adiponectin mediates heat-shock protein 90 and eNOS complex formation, required for the maximal eNOS activation (Xi et al., 2005). Adiponectin decreases endothelial apoptosis, senescence and dysfunction induced by high plasma glucose, oxidized low-density lipoprotein (oxLDL) and palmitate - the key mediators of diabetes and obesity (Xiao et al., 2011; Plant et al., 2008; Kim et al., 2010; Zhao et al., 2016). In endothelial cells, adiponectin down‐regulates pro-apoptotic and pro‐oxidants like caspase‐3 and NADPH‐oxidases, which are involved in atherogenesis (Yuan et al., 2019). Furthermore, adiponectin promotes endothelial repair and angiogenesis by increasing the number and activity of EPC, and mobilizing these progenitors from the bone marrow or spleen into the systemic circulation (Shibata et al., 2008). Adiponectin supplementation improves the anti-inflammatory potential of EC by restraining the expression of cell adhesion molecules, selectins, and chemokines like monocyte chemoattractant protein −1 (MCP-1) and interleukin (IL) −8, which in turn attenuate endothelial hyperpermeability and monocyte adherence to EC (Lovren et al., 2010). Moreover, treatment of ApoE^−/− mice and rabbits with recombinant adenovirus expressing human adiponectin minimized the expression of the adhesion molecules on the endothelium and reduced atherosclerotic burden (Okamoto et al., 2011; Li, Sun, et al., 2007; Okamoto et al., 2002). Several clinical studies have implied an inverse corelation between serum adiponectin level and endothelial injury (Xu, Tian, and Zhou 2018; Malyszko et al., 2005). Therefore, adiponectin may represent a potential versatile therapy for obesity, IR and atherosclerosis in humans.

1B. Adiponectin inhibits the differentiation of VSMC into osteoblasts and attenuates vascular calcification and stiffness:

Adiponectin mediates cardioprotective effects by mitigating cardiovascular pathologies such as vascular calcification and neointimal formation in arteries and valves (Ouchi, Shibata, and Walsh 2006) in diabetic and chronic kidney diseases (Okamoto et al., 2011). Vascular calcification and neointimal formation, unless treated in advance, lead to vascular wall stiffness often resulting in ischemia, thrombosis and cardiac hypertrophy, which cause heart failure (HF), stroke and renal failure (Albiero, Menegazzo, and Fadini 2010; Lacolley et al., 2012; Lusis et al., 2000; Jayalath, Mangan, and Golledge 2005; Jablonski and Chonchol 2013). Low plasma adiponectin levels were reported to be corelated with progression of coronary artery calcification in type 1 diabetic and nondiabetic subjects independent of other cardiovascular risk factors (Maahs et al., 2005). Studies in Adipoq^−/− mice further demonstrated increased incidence of vascular calcification, and neointimal formation via p38 mitogen activated protein kinase (MAPK) activation (Luo et al., 2009; Rattazzi et al., 2005; Moore and Hui 2005). Supplementation of recombinant adiponectin has been shown to attenuate neointimal thickening in mechanically injured arteries (Matsuda et al.,2002). It was further shown to prevent calcification in VSMC treated with tumor necrosis factor-α (TNF-α) (Son et al., 2008) and β-glycerophosphate (β-GP) (Zhan et al., 2014), a serine-threonine phosphatase inhibitor that drives osteogenic differentiation from VSMC. Adiponectin prevents hardening of vessel walls by inhibiting the expression of calcium and phosphorous binding proteins - alkaline phosphatase, osterix, osteopontin and osteocalcin (Luo et al.,2009). Additionally, adiponectin inhibits osteoblast differentiation by suppressing the expression of key transcription factors such as Runt-related transcription factor 2 (Runx2) and bone morphogenic protein −2 (BMP2) (Lu et al., 2019; Luo et al.,2009; Zhan et al., 2014), which are involved in the pathogenesis of vascular calcification. Adiponectin treatment has been shown to prevent conversion of VSMC towards osteoblast-like phenotype and mineralized matrix formation, key features in the progression of vascular calcification, by inhibiting the mTOR and JAK2-STAT3 signaling pathways (Zhan et al., 2014; Lu et al., 2019). Although, adiponectin regulates VSMC calcification by regulating various signaling pathways in vitro, the possibility of increased renal calcium and phosphate excretion in improving vascular function by restricting calcification in vivo should also be considered (Rutkowski et al., 2017). Adiponectin inhibits insulin-like growth factor-1-induced VSMC migration and proliferation, and the release of VSMC matrix vesicles, the major sources of microcalcification in neointima and vascular calcification (Motobayashi et al., 2009). In addition, adiponectin inhibits VSMC apoptosis that results from the mechanical forces caused by stretch, irregular blood pressure and blood flow (Lu et al., 2015; Spiguel et al., 2010; Shi and Tarbell 2011). VSMC apoptosis is one of the major factors inducing plaque vulnerabilities in atherosclerosis (Clarke et al., 2006; Kockx and Knaapen 2000). In contrast to well-understood beneficial roles of adiponectin in several diseases, serum adiponectin levels increase in patients with HF, indicating its complicated roles in CVD (Bai et al., 2019; Baltruniene et al., 2017). Although adiponectin may represent a potential candidate for treatment of vascular calcification, careful studies investigating its protective mechanisms in CVD are required.

1C. Adiponectin promotes anti- atherosclerotic effects by enhancing cholesterol efflux from plaque macrophages:

Overexpression of the adiponectin gene has been shown to protect ApoE^−/− mice from atherosclerosis by reducing lesion formation in the aortic sinus (Okamoto et al., 2002). Macrophages from adiponectin-transgenic mice showed lower expression of proteins like scavenger receptor-A (SR-A), CD36, acyl-CoA and cholesterol-acyltransferase one (ACAT1) that are involved in cellular oxLDL uptake, resulting in diminished lipid accumulation in macrophages (Luo et al.,2010). Adiponectin enhances the expression of cholesterol efflux transporters such as ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette sub-family G member 1 (ABCG1), and promotes apoA-I/HDL-mediated cholesterol efflux via activating peroxisome proliferator-activated receptor (PPAR)-γ/ liver X receptor -α in mice (Hafiane, Gasbarrino, and Daskalopoulou 2019). By suppressing aortic angiotensin-II (Ang-II) receptor expression, adiponectin inhibits Ang II-mediated macrophage accumulation and expression of pro-inflammatory genes such as TNF-α, MCP-1, IL-6 and IL-12 (van Stijn et al., 2014). Hypoadiponectinemia was identified as a robust predictor of reduced cholesterol efflux capacity in a study that included 683 participants irrespective of BMI and fat distribution (Marsche et al., 2017). Moreover, a strong corelation was noted between decreased serum adiponectin levels and impaired cholesterol efflux capacity in diabetic patients (Yanai and Yoshida 2019). Treatment of macrophages with recombinant adiponectin led to a reduction of ROS and switch towards an anti-inflammatory phenotype (Ohashi et al.,2010). Thus, by accelerating high density lipoprotein (HDL) biogenesis, effective cholesterol disposal from foam cells and attenuating maladaptive inflammatory potential of macrophages in atherosclerotic lesions, adiponectin may have therapeutic potential for atherosclerosis prevention and management.

1D. Adiponectin improves cardiac function by modulating cardiac fibrosis and hypertrophy:

Adiponectin has direct beneficial effects on cardiomyocytes in several pathological cardiac conditions, including ischemia-reperfusion (I/R) injury, congestive HF and cardiac hypertrophy (Hopkins et al., 2007). By attenuating cardiomyocyte apoptosis following I/R in mice, adiponectin reduces adverse cardiac remodeling and myocardial infarct size, and improves cardiac function (Zhao et al., 2018). Adiponectin over-expression reverses cardiac hypertrophy induced by endothelin-1 (Ouchi, Shibata, and Walsh 2006). Adiponectin binds to its receptors- AdipoR1 and AdipoR2, and activates PPARα, an important signaling molecule downstream of 5’ adenosine monophosphate-activated protein kinase (AMPK), which plays a protective role against cardiac hypertrophy and fibrosis by down-regulating oxidative stress and inflammation (Thundyil et al., 2012; Kim and Park 2019; Park et al., 2016). Moreover, in Adipoq^−/− mice, cardiomyocytes were protected from I/R injury-induced apoptosis with the supplementation of exogenous adiponectin (Tao et al., 2007). However, the cardioprotective effects of adiponectin have been contradicting in different disease models. Increased adiponectin levels were reported in severe HF (Menzaghi and Trischitta 2018; Forsblom et al., 2011; Francischetti et al., 2020). The elevation of adiponectin levels in HF may be because of hyper-catabolic state in severe HF as adiponectin levels increase in HF patients only in the presence of cachexia (Springer, Anker, and Doehner 2010). It is unclear whether adiponectin contributes to HF, or its increase is part of a compensatory mechanism. Recent studies have shown that chronic activation of adiponectin has adverse systemic and cardiovascular effects (Sente et al., 2016). Hence, the use of adiponectin as a clinical biomarker in HF is controversial. Therapeutic usage of adiponectin in HF patients still awaits confirmation by further investigations and clinical trials.

2. Omentin:

Omentin, also known as intelectin-1, is a novel adipocytokine and glycoprotein containing 313 amino acids (Zhou et al., 2017). It is identified as a soluble galactofuranose-binding lectin with no identified receptor so far (Zhou et al., 2017). In humans, omentin expression varies in different organs. The protein is mainly expressed in VAT with detectable concentrations of 100 to 800 ng/ml in plasma (Escote et al., 2017). A few studies have confirmed the crucial roles of omentin in metabolism and insulin sensitivity in addition to its anti‐inflammatory and cardiovascular protective effects. Lower levels of serum omentin-1 were identified in obese children, and patients with gestational diabetes mellitus and impaired glucose tolerance (Pan et al.,2019; As Habi et al.,2019). Hence, it can be used as a potential metabolic biomarker (Zengi et al.,2019). However, no significant difference in omentin-1 concentrations was observed between patients with type 1 diabetes mellitus and healthy controls in a meta-analysis of 42 eligible studies (Pan et al., 2019). Negative corelations between serum omentin levels and BMI, fasting insulin, homeostatic model assessment-IR and systolic blood pressure (Onur et al.,2014; Elsaid et al., 2018) in obesity further strengthen the protective role of omentin in metabolic complications (Moreno-Navarrete et al., 2010). With respect to cardiovascular complications, patients with ischemic stroke and unstable carotid plaque, who have high mortality, harbor lower levels of serum omentin-1 (Wu et al., 2019). Omentin protects the vasculature through its pleiotropic actions on EC, SMC, macrophages and cardiomyocytes. Figure 1 explains the potential benefits of omentin in vasculature and the possible mechanisms of how omentin improves vascular health. Omentin prevents the senescence and activation of EC, inhibits VSMC proliferation, curbs macrophages infiltration and foam cells accumulation, and maintains cardiomyocyte function to promote cardiovascular health by preventing atherosclerosis and improving cardiac vasorelaxation.

2A. Omentin inhibits vascular endothelial cell activation and senescence, and improves cardiovascular health:

Omentin stimulates vasodilation in isolated blood vessels (Yamawaki et al., 2010) and reverses impaired relaxation of mouse aortas (Liu et al., 2020) after high-glucose insult and cytokine stimulation. Free fatty acids, like palmitate, which are the hallmarks of obesity and diabetes, impede human umbilical vein endothelial cells (HUVEC) proliferation and migration, which can be reversed with omentin treatment (Chen et al., 2020). Additionally, omentin supplementation attenuated neointimal thickening in mechanically injured arteries by enhancing the survival of EC (Uemura et al., 2015). At the cellular level, the effects of omentin could be mediated by attenuating G1 phase cell-cycle arrest and also by reducing stimulus-induced expression of senescent factors such as caveolin-1, p21 and plasminogen activator inhibitor (PAI)-1, and p53 acetylation (Chai et al., 2020). By inhibiting leukocyte adhesion molecules and procoagulant factors, omentin prevents endothelial-monocyte interactions (Yamawaki et al., 2011). This was confirmed by over-expressing omentin in HUVEC cells, which decreased THP-1 monocyte adherence in response to injury (Chen et al., 2020). Interestingly, omentin protects EC from oxidative stress-related cellular injury via several intracellular defense mechanisms that involve increased expression and activities of anti-oxidant enzymes such as glutathione peroxidase (Binti Kamaruddin et al., 2020). Recent evidence suggests that omentin activates the NO signaling cascades and cGMP, which regulate vascular tone, and exert anti-inflammatory and anti-thrombotic effects (Kutlay, Kaygisiz, and Kaygisiz 2019). Mechanistically, many beneficial effects of omentin are mediated by activating eNOS in an AMPK-dependent manner. However, the possible role of upstream kinases like liver kinase B1, calcium-calmodulin-dependent kinase 2 and transforming growth factor-β-activated protein kinase-1, which phosphorylate the critical Thr172 activating site of the AMPK, cannot be excluded in the beneficial role of omentin. Hence, the current literature on omentin is highly supportive of omentin therapy to improve endothelial function for treating various vascular infirmities.

2B. Omentin ameliorates arteriosclerosis by diminishing VSMC calcification and proliferation:

Global omentin knockout mice exhibited increased arterial calcification following 5/6-nephrectomy and high phosphate diet (5/6 NTP) administration. Overexpression of omentin attenuated osteoblastic differentiation and mineralization of VSMC in vitro and 5/6 NTP-induced arterial calcification (Xu et al., 2019). Fat-specific human omentin transgenic mice exhibited reduced neointimal thickening, intimal hyperplasia and vascular cell growth by decreasing the frequencies of proliferating and migrating VSMC in mechanically injured arteries (Uemura et al., 2015). Supplementation of exogenous human omentin reduced VSMC calcification by suppressing the expression of Runx2, collagen I and osteocalcin, and diminished osteoblastic differentiation by inducing PI3K/Akt activation in vitro. Omentin ameliorated arterial calcification in vivo by inhibiting the receptor activator of nuclear factor (NF)-κ B ligand (RANKL) signaling pathway, which regulates osteoclast differentiation and activation (Xie et al., 2011). Additionally, omentin has been shown to reduce atherogenesis by suppressing Ang II-induced migration, and platelet-derived growth factor-BB-induced proliferation and collagen-1 and −3 expression in human aortic SMC (Watanabe et al., 2016). Treatment with human omentin at physiological concentrations was shown to suppress platelet-derived growth factor-BB (Kazama, Okada, and Yamawaki 2014) and heparin‐binding endothelial growth factor (Uemura et al., 2015)-induced abnormal growth of VSMC. Omentin treatment was further shown to inhibit osteoblastic differentiation of calcifying VSMC (Duan et al., 2011), a subpopulation of aortic SMC, which is putatively involved in vascular calcification. The low levels of circulating omentin observed in obesity corelate with vascular calcification. These findings suggest that lower omentin levels in obese subjects contribute to the development of arterial calcification, and omentin plays a protective role against arterial calcification.

2C. Omentin prevents atherogenesis by mitigating macrophage infiltration and foam cells formation:

ApoE^−/− omentin transgenic mice exhibited a significant reduction of atherosclerotic plaque volumes in the aortic sinus when compared with the control ApoE^−/− mice despite of similar lipid levels in plasma (Hiramatsu-Ito et al., 2016). Aortas of these transgenic mice displayed decreased inflammatory responses like macrophage accumulation and mRNA expression of pro-inflammatory mediators including TNF-α, IL-6 and MCP-1 (Hiramatsu-Ito et al., 2016). Involvement of the Akt signaling, which promotes anti-inflammatory phenotype of macrophages, needs to be studied in atherosclerotic lesions of omentin transgenic mice (Hiramatsu-Ito et al., 2016). Macrophage apoptosis plays a crucial role in atherogenesis (Hiramatsu-Ito et al., 2016). TUNEL staining of macrophages in atherosclerotic lesions revealed that ApoE^−/− omentin transgenic mice had a lower frequency of apoptotic macrophages in atherosclerotic lesions when compared with ApoE^−/− mice (Hiramatsu-Ito et al. 2016). Treatment of human monocyte-derived-macrophages with physiological concentrations of human omentin protein reduced lipid droplets and cholesteryl ester content (Hiramatsu-Ito et al.,2016). Omentin prevents oxLDL-induced foam cell formation by downregulating the proteins facilitating lipid uptake, such as CD36, SR-A, and ACAT1, and enhancing neutral cholesterol ester hydrolase and reverse cholesterol transport protein (ABCA1) in macrophages. Omentin treatment also exhibits beneficial effects against atherogenesis by reducing macrophages infiltration and promoting anti-inflammatory phenotype (Watanabe et al., 2016; Tan et al., 2019).

2D. Omentin improves cardiac vasorelaxation and relieves cardiac dysfunction:

Omentin treatment improves cardiac function by decreasing left ventricular developed pressure and maximal rate of pressure development, the indices of cardiac contractility, in isolated rat hearts (Kutlay, Kaygisiz, and Kaygisiz 2019).This was accompanied by decreased expression of L-type Ca²⁺ channel levels that passes inward Ca²⁺ current and triggers calcium release from the sarcoplasmic reticulum by activating ryanodine receptor 2 from cardiomyocytes (Kutlay, Kaygisiz, and Kaygisiz 2019). Systemic administration of human omentin into mice decreased myocardial infarct size, infarct area at risk, myocardial ischemic damage, infarct area/left ventricular ratio, myocyte apoptosis and cardiac hypertrophy after I/R via multiple mechanisms (Kataoka et al., 2014). The protective role of omentin against cardiomyocyte apoptosis is mediated by triggering intracellular GLUT4-containing membrane vesicles trafficking to the sarcolemma membrane and subsequent utilization of glucose and glycolytic ATP (Shao and Tian 2015). Furthermore, through AMPK activation, omentin could phosphorylate 6-phosphofructo-2-kinase resulting in increased fructose 2,6-bisphosphate concentration that allosterically activates phosphofructokinase-1, the rate-limiting step in glycolysis for the survival of cardiomyocytes. Adenoviral gene transfer of omentin followed by arterial wire injury in mice reduced neointimal thickening and frequencies of bromodeoxyuridine-positive proliferating cells in injured arteries (Uemura et al., 2015). Furthermore, circulating levels of creatine phosphokinase, a marker of heart injury, were lower in adenoviral-omentin-treated mice after cardiac reperfusion injury (Kataoka et al.,2014). These protective properties of omentin are further substantiated by other studies showing that increased levels of plasma omentin in humans corelate with higher myocardial index scores and lower frequency of ischemic changes in electrocardiogram (Kataoka et al., 2014; Pourbehi et al.,2016).

3. Resistin:

Resistin was originally discovered in adipocytes of mice displaying IR and subsequently named resistin. It belongs to the resistin-like molecules (RELM) family comprised of RELM-α, RELM-β and RELM-γ (Zhou et al., 2021). The expression levels of resistin are positively associated with fat mass and contribute to obesity and diabetes mellitus. Elevated resistin levels are associated with incidence and severity of coronary artery disorders, HF and atherosclerosis (Gencer et al., 2016). This adipocytokine exacerbates adverse cardiovascular events by diverse functions like enhancing endothelial injury, inflammatory response and lipid accumulation (Verma et al., 2003). Systemic levels of resistin are now attracting much attention as they positively corelate with the presence of advanced atherosclerotic plaques in the human aorta and carotid arteries (Yang et al.,2018). Several perspective studies have shown that resistin aggravates atherosclerosis and cardiac-remodeling after myocardial-infarction (Piestrzeniewicz et al., 2008; Lubos et al., 2007). Elevated serum resistin levels are observed in patients presenting with unstable angina, non ST-segment elevation MI and ST-segment elevation MI, representing resistin as a diagnostic marker (Zhang et al., 2017). Figure 2 defines the pathological role of resistin in EC, SMC and macrophages present in the vasculature, and the associations between resistin and cardiovascular complications. Resistin potentially impairs vasodilation, aggravates atherosclerosis and initiates cardiac fibrosis via enhancing endothelial permeability, VSMC proliferation, foam cells accumulation and reducing contraction and relaxation velocities of cardiomyocytes.

Figure 2:

Pro-inflammatory adipocytokines role in cardiovascular pathology.

3A. Resistin enhances vascular diapedesis by compromising endothelial permeability:

Resistin promotes arterial vasoconstriction by enhancing the production of endothelial derived vasoconstrictive agents such as endothelin-1, von Willebrand factor and PAI-1, and inhibiting vasoactive reagents like prostacyclin and endothelium-derived relaxing factor/NO (Li, Wang, et al., 2007; Dick et al., 2006). Studies showed that high concentrations of resistin generated in conditional media by adipocytes obtained from patients with acute coronary syndrome profoundly increased endothelial permeability (Burnett et al., 2005). This makes the endothelium more prone for leukocyte attachment and their extravasation into the sub-endothelial space, resulting in narrowing of the vessel lumen accompanied by impediment of blood flow and eventually causing MI or stroke. Studies on vascular function and insulin-evoked vasorelaxation identified that resistin administration impairs dose-dependent insulin-mediated vasodilation by reducing eNOS activity (Gentile et al., 2008). These catastrophic effects were further noticed with resistin treatment in vivo in cultured aortic EC and porcine coronary rings (Dick et al., 2006) due to depressed eNOS protein and its phosphorylation (Kougias et al., 2005). Additionally, this adipocytokine interrupts the pro-vasorelaxant pathway of EC by suppressing the phosphorylation of insulin receptor substrate-1 tyrosine/serine (Gentile et al., 2008). This ultimately alters insulin receptor substrate-1 interaction with PI3K leading to reduced PI3K activity and its downstream signaling, which is required for insulin sensitivity (Gentile et al., 2008). By reducing the activities of anti-oxidants, such as catalase and superoxide dismutase, resistin impairs the mitochondrial membrane potential of EC, leading to increased apoptosis and senescence (Chen et al., 2010). Moreover, by activating pro-inflammatory signaling pathways like NF-κB, MAPK, p38 and JNK, resistin enhances the production of pro-inflammatory cytokines, adhesion molecules (ICAM-1, VCAM-1) and chemokines, such as MCP-1, in EC (Gao et al.,2016). This makes arteries more vulnerable for plaque development. Hence, it is imperative to identify the strategies that improve endothelial functions in patients with higher systemic resistin levels for efficacious treatment of cardiovascular abnormalities.

3B. Resistin aggravates vascular pathologies by enhancing the phenotypic switch of VSMC:

Human atheromas are associated with higher levels of resistin, SMC-associated protein fractalkine (CX₃CL1) and its cognate receptor CX₃CR1. CX₃CL1, a typical chemokine, which functions both as a chemoattractant and adhesion molecule, facilitating monocyte and T cell transmigration in atherosclerotic lesion-prone areas (Gan et al., 2013). CX₃CL1 and CX₃CR1 expression is elevated in resistin-stimulated SMC and enhances SMC-induced monocyte transmigration (Gan et al., 2013). These associations denote that resistin has prominent role in influencing SMC towards pro-inflammatory phenotype in atherosclerotic plaques. This adipocytokine initiates neointimal hyperplasia and ultimately propagates restenosis by stimulating the production of matrix metalloproteinases (MMP), particularly MMP-2 and MMP-9, which enhance SMC migration and decrease overall plaque stability (Cho and Reidy 2002). Moreover, resistin induces SMC proliferation by decreasing p53, p21, and p27 levels through activating the MAPK and Akt signaling pathways (Calabro et al., 2004; Hirai et al., 2013). Mounting evidence suggests that in obesity, higher levels of resistin contribute to SMC proliferation and promote development of obesity-related vascular malformations by upregulating the expression of pro-inflammatory serine/threonine kinases like serum and glucocorticoid-regulated kinase 1, and phosphorylating the serine 422 residue (pSGK1) via the TLR4 and PI3K signaling (Scott et al., 2016). This enhancement in VSMC proliferation and migration exerted by resistin contributes to abnormal vascular changes.

3C. Resistin increases foam cells accumulation and destabilizes atherosclerotic plaques:

Higher transcript and protein levels of resistin in CD68-positive monocytes/macrophages have been noticed in atherosclerotic plaques of carotid arteries, atherosclerotic aneurysms and coronary artery disorders (Jung et al.,2006). Resistin overexpression accelerates atherosclerotic plaque growth and destabilizes the lesions by enriching macrophage accumulation (Cho et al., 2011). Resistin remarkably exacerbates the pro-atherogenic environment in arteries by enhancing the expression of cell adhesion molecules in EC, increasing very late antigen-4 and integrins in monocytes, promoting monocyte-EC adhesion and retaining macrophages (Cho et al., 2011). Resistin further deteriorates pathophysiology of the vascular wall containing atherosclerotic plaques by triggering pro-inflammatory macrophage development through the PKC-ε signaling (Zuniga et al., 2017). By activating the TLR4/NF-κβ signaling, resistin promotes antigen presentation by macrophages and induces the iNOS/NO signaling, exerting immune injury in atherosclerotic plaques (Zhou et al., 2021). Resistin promotes lipid uptake and accumulation in macrophages to facilitate foam cell formation (Xu et al., 2006; Lee et al., 2009). By decreasing cholesterol efflux either by inhibiting expression or increased degradation of ABCA1 and ABCG1 proteins, resistin provokes foam cell development (Lee et al., 2009). Besides adipose tissue, which is the primary source of resistin, infiltrated macrophages are also the prominent sources of resistin in pathological conditions such as aneurysms (Jung et al., 2006). In vitro, monocytes/macrophages express high concentrations of resistin mRNA compared to EC and VSMC (Jung et al., 2006). Other than resistin, RELMβ is also expressed abundantly in foam cells within plaques and contributes to atherosclerosis development via inflammation and lipid accumulation (Kushiyama et al., 2013). Deletion of RELMβ attenuates Ang II-induced aortic abdominal aneurysm formation in ApoE^−/− mice by inhibiting pro-inflammatory cytokines and MMPs via MAPK and JNK activation (Meng et al., 2017). These results represent that in addition to resistin, RELMβ is also a novel target for therapeutic interventions of aneurysms and coronary artery disorders.

3D. Resistin impairs cardiomyocyte function and worsens cardiac fibrosis:

Studies have shown that resistin induces cardiac hypertrophy and remodeling by impairing glucose handling in cardiomyocytes (Kim et al., 2008). In cardiomyocytes, both mouse and human resistin directly inhibits insulin-stimulated glucose uptake via mechanisms that involve altered GLUT4 vesicle trafficking (Graveleau et al., 2005). Long-term in vivo overexpression of resistin in male Sprague-Dawley rats with adenovirus overexpressing resistin was associated with increased ratio of LV/ body weight, increased end-systolic LV volume, decrease in LV contractility, increased fibrosis, and elevated mRNA levels of collagen, fibronectin and connective tissue growth factor compared to controls (Chemaly et al., 2011). Furthermore, overexpression of resistin in neonatal rat cardiomyocytes increased myocyte surface area and inflated hypertrophy by augmenting oxidative stress, atrial natriuretic factor and β-myosin heavy chain levels, and inciting hypertrophic signal transduction processes, namely MAPKs (Chemaly et al., 2011). In adult cardiomyocytes, resistin overexpression significantly altered myocyte mechanics by dampening cell contractility and relaxation velocity through impaired cytoplasmic calcium clearance, depressed calcium transients and alterations in myofilament activation. This leads to impaired myocyte relaxation and hypertrophy, which are common in pressure-overload and HF mouse models (Kim et al., 2008).

4. Leptin:

Leptin is a 16-kDa, non-glycosylated protein encoded by obese (ob) gene, and is mainly synthesized and secreted by adipocytes (Ramos-Lobo and Donato 2017). Leptin’s action through its receptor (Lep-R) has been documented in a variety of tissues (Ramos-Lobo and Donato 2017). Leptin acts as both a hormone and cytokine, linking nutritional status with neuroendocrine and immune functions by regulating food intake and energy expenditure (Park and Ahima 2015). Besides regulating metabolism, leptin participates in the modulation of other physiological processes, such as angiogenesis (Park et al., 2001), wound healing (Tadokoro et al., 2015), and central and peripheral endocrine actions (Margetic et al., 2002). Reduced levels of leptin as found in malnourished individuals is linked to increased risk of infection and reduced cell‐mediated immune responses (Maurya et al., 2018). Conversely, leptin can be both a cause and consequence of many vascular complications. Elevated circulating leptin levels positively corelate with VAT mass, BMI and body weight, provoking a low‐grade inflammatory state in obesity (Francisco et al., 2018). Furthermore, leptin associates positively with various vascular complications such as hypertension, MI, stroke, venous thrombosis, dilated cardiomyopathy and neointimal hyperplasia (Seufert et al., 2004; Beltowski et al., 2006; Correia and Haynes 2004; Koh, Park, and Quon 2008). Hyperleptinemia is a predictor of high risk of CVD and also serves as an afflicting biomarker in HF (Yanavitski and Givertz 2011). In a large cohort of healthy individuals, independent of established cardiovascular risk factors, a positive relationship was observed between coronary calcification and leptin levels, further confirming leptin’s devastating role (Liu et al., 2019). Several plausible mechanisms for leptin-induced cardiovascular complications have been suggested, including endothelial dysfunction (Huby, Otvos, and Belin de Chantemele 2016), lipoprotein oxidation (Porreca et al., 2004), platelet activation (Elbatarny and Maurice 2005) and blood coagulation in arteries (Schafer and Konstantinides 2014). Leptin receptors are highly expressed in all cell types involved in vascular pathologies including EC (Hubert et al., 2017), SMC (Ryan et al., 2016), macrophages (Surmi et al., 2008) and cardiomyocytes (Hall, Harmancey, and Stec 2015). Leptin has been implicated as a key upstream mediator of the pathways associated with CVD. Figure 2 describes the pathogenesis of leptin with respect to EC dysfunction, abnormal proliferation of SMC and inflammatory potential of macrophages in chronic CVD such as atherosclerosis and vascular calcification. Leptin accelerates the onset of cardiovascular complications by inducing endothelial damage, promoting VSMC migration, stimulating pro- inflammatory potential of macrophages and impairing cardiomyocytes function.

4A. Leptin induces endothelial dysfunction and promotes the onset of cardiovascular complications:

Leptin has profound vasoactive effects by enhancing the production of ednothelin-1 via increased binding of transcription factor activator protein-1 to the promoter region of endothelin-1 in EC (Quehenberger et al., 2002). Numerous studies have investigated the potential mechanisms responsible for leptin-induced endothelial dysfunction. Especially in HF patients, the expression levels of leptin and its receptor were corelated with the increased expression of the components in the renin-angiotensin-aldosterone system, such as angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin receptors (AT1 and AT2) and aldosterone synthesis genes, that enhances HF pathogenesis (Dadarlat et al., 2018). Leptin enhances endothelial dysfunction by increasing oxidative stress and upregulates pro-inflammatory cascades including the adhesion, chemotactic and growth factor pathways via activating NF-κB (Teixeira et al., 2017). Hyperleptinemia observed during obesity triggers an endothelial NO/ONOO⁻ imbalance, the characteristic of dysfunctional endothelium, by reducing L-arginine and inducing eNOS uncoupling. This results in the reduction of bioavailable NO and elevated concentrations of cytotoxic O2⁻ and ONOO⁻ radicals (Korda et al., 2008). Deletion of the leptin receptors in EC has been shown to enhance autophagosome formation and autophagy by mitigating mTOR activity in response to chronic cardiac pressure overload in mice. These contribute to improved angiogenic sprouting, stabilization of cardiac microvasculature, and reduction of inflammation and fibrosis (Gogiraju et al., 2019). Intriguingly, Frühbeck and others demonstrated that leptin infusion induces vasodilation with increased serum nitrate concentrations in the aorta by phosphorylating eNOS and enhancing NO release (Vecchione et al., 2002). Intra-arterial administration of leptin showed a similar vasoactive response independent of NO in humans (Matsuda et al., 2003). These findings are also supported by another study (Vecchione et al., 2002), emphasizing the importance of leptin as a potent endothelial NO source to improve vasodilation (Lembo et al., 2000).

4B. Leptin exacerbates VSMC migration/proliferation and afflicts cardiovascular health:

Leptin has been implicated as a key upstream mediator of the pathways associated with enhanced VSMC hypertrophy, proliferation and contraction (Noblet et al., 2016). Leptin has been shown to promote the onset and development of variety of CVD including atherosclerosis (Dubey and Hesong 2006), hypertension (Bravo et al., 2006), neointima formation (Schroeter et al., 2013) and vascular stenosis (Liu et al., 2019). The stimulatory effect of leptin on VSMC proliferation is mediated through its binding to the leptin receptor (Lep-R) and also by inducing the expression of cyclin D1, which promotes cell proliferation through the MAPK pathway (Huang et al., 2010). The magnitude and chronicity of VSMC proliferation were enhanced by endothelin-1 stimulation and strongly corelated with concurrent increased endothelin type A receptor in leptin-treated cells indicating the role of this adipokine in accelerating atherogenesis (Koh, Park, and Quon 2008). In VSMC, upon leptin binding, Lep-R enhances MMP-2 and MMP-9 levels via increased binding of the transcription factor activator protein-1 to the promoter regions of the matrix metalloproteinases (Liu et al., 2018). Hence, in advanced plaques, leptin could destabilize the lesions and increase the likelihood of plaque rupture by inducing MMP expression and degrading collagen in the shoulder regions of fibrous caps.

4C. Leptin activates vascular macrophages and increases prevalence of atherogenesis and atherosclerosis severity:

With structural resemblance to IL-2 and growth hormone 1, leptin modulates both innate and adaptive immune responses (La Cava et al., 2017). This adipokine triggers the pro-inflammatory function of macrophages and thereby increases the production of several pro-inflammatory cytokines, such as IL-2, IFN-γ, TNF-α and CC-chemokine ligands (CCL3, CCL4, and CCL5), by stimulating the JAK2-STAT3 pathway (Maurya et al., 2018). A significant positive corelation was observed between plasma leptin levels and NADPH oxidase activity in obese patients (Fortuno et al., 2010). Consistently, leptin-treated human peripheral blood mononuclear cells produced heightened levels of ·O2⁻ by promoting the translocation of p47phox subunit of the NADPH oxidase from the cytosol to the cell membrane through the activation of the PI3K/PKC signaling pathway (Fortuno et al., 2010). The resulting increase in leptin-induced ·O2⁻ production was higher in obese group than in the control group (Fortuno et al., 2010), suggesting that leptin significantly enhances secretion of free radicals from macrophages, enhancing a toxic environment in vessel wall. Leptin also promotes atherogenesis by enhancing adhesion of monocytes to the laminins of the endothelium (Sarigianni et al., 2010). This adipokine intensifies chronic accumulation of cholesteryl esters in macrophages by increasing the expression of ACAT-1 (Hongo et al., 2009) and subsequent transformation of macrophages into foam cells. Leptin may regulate monocyte extravasation into the sub-endothelial space by increasing surface expression of the integrins to promote their adherence and interaction with the cell adhesion molecules in EC (Dubey and Hesong 2006). However, detailed mechanisms addressing the role of leptin in monocyte infiltration need to be studied. In addition, leptin enhances CD36 scavenger receptor expression and oxLDL uptake through PI3K/PKC signaling activation (Konstantinidis et al., 2009). As observed in murine macrophage J774A.1 cell line, leptin can increase iNOS and COX-2 activities, the potential markers of macrophage activation and inflammation (Raso et al., 2002). It was further demonstrated that leptin deteriorates vascular health in response to pro-inflammatory Th1 cytokines like IFN-γ (Raso et al., 2002). Increased immunoreactivity for Lep-R, VEGF and MMPs has been shown in atherosclerotic plaques, predominantly in macrophages/foam cells and the endothelial lining of neointima, suggesting that leptin signaling has a prominent role in the progression of atherosclerotic lesions (Kang et al., 2000). Local application of leptin accelerated growth of abdominal aortic wall in ApoE^−/− mice, which was accompanied by increased peri-adventitial macrophage accumulation and enhanced MMP-2 and 9 expression (Tao et al.,2013). The treatment of Ldlr^−/−;Lep^−/− mice with leptin diminished plaque area in the aortic root, decreased adipose tissue macrophage infiltration, and suppressed IL-6 and MCP-1 levels in plasma (Hoffmann et al., 2019). Further investigations to elucidate the mechanisms by which leptin influences the production of MMPs by macrophages/foam cells in atherosclerotic plaques, and leptin’s effect on plaque rupture and stability are required.

4D. Leptin triggers heart failure by exerting metabolic disturbances in cardiomyocytes:

Several studies have shown a direct link between serum leptin concentrations and cardiac remodeling. The role of leptin in the development of cardiac hypertrophy has been controversial. Epidemiologic studies in humans have demonstrated positive corelations between plasma leptin levels and increased cardiac mass and LV wall thickness while other studies observed anti-hypertrophic effects of this adipokine (Ghantous et al., 2015; Hou and Luo 2011). Although the mechanisms by which leptin may contribute to LV hypertrophy are poorly understood, chronic infusion of leptin has been shown to increase arterial blood pressure, cardiac afterload and pro-inflammatory cytokine signaling, promoting hypertrophy (Allison et al., 2013). In obesity, leptin influences the uptake of basal and insulin-stimulated fatty acids such as palmitate by increasing CD36 and fatty acid transport protein 1 levels. This leads to intracellular lipid accumulation and lipotoxic damage in HF (Palanivel et al., 2006). However, it is also known that leptin stimulates fatty acid and glucose metabolism in cardiomyocytes, prevents steatosis and protects against apoptosis (Hall, Harmancey, and Stec 2015). In 2003, Barouch et al. examined the role of leptin in cardiac hypertrophy. They observed the development of LV hypertrophy with significantly increased LV mass, LV wall thickness and cardiomyocyte hypertrophy in Lep^−/− and LepR^−/− mice (Barouch et al., 2003). In summary, the reports on the effects of leptin on cardiac growth and hypertrophy are conflicting. Although hyperleptinemia is associated with cardiac hypertrophy, the presence of many confounding factors makes it difficult to establish a causal relationship. Animal studies suggest that hyperleptinemia does not directly cause cardiac hypertrophy but may somehow play a fundamental role in cardiac structural alterations in response to obesity and the associated metabolic changes (Abel, Litwin, and Sweeney 2008). Additional studies are required to unveil the mechanisms by which leptin regulates cardiac remodeling.

Adipokines in vascular ageing:

Ageing is a critical factor that changes the body composition and energy homeostasis (Chung et al., 2021; Al-Sofiani et al., 2019; McHugh et al., 2018; JafariNasabian et al., 2017). Ageing is the most important underlying risk factor in the development of many chronic conditions, including obesity, diabetes and cardiovascular disease (McHugh and Gil 2018; North et al., 2012; Gunasekaran and Gannon 2011; Iozzo et al., 1999). Moreover, ageing and CVD are highly interconnected and share many common pathways including weight gain, increased volume of visceral adipose depot and systemic inflammation (Costantino et al., 2016; Assar et al., 2016, Després et al., 2007, Xu et al., 2020; Nicklas et al., 2004). Beyond its active role in maintaining systemic energy metabolism, and lipid and glucose homeostasis, adipose tissue has profound effects on health and ageing by changing the levels of adipokines such as adiponectin, omentin, leptin, resistin etc (Picard and Guarente 2005; Galic et al., 2010, Arai et al., 2011 and 2019; Maeda et al., 2020). These adipokines, by modulating multiple biological functions including peripheral insulin sensitivity, lipid profile and inflammation, contributes to age-related metabolic changes, physiological integrity, cardiovascular health and longevity (Matsuzawa et al., 2006, Rasouli and Kern 2018; Arai et al., 2019). With the age advancing, blood concentrations of adiponectin and omentin, the two anti-inflammatory adipocytokines that improve insulin sensitivity likely decrease and conversely corelate with BMI, vascular senescence, vasodilation, fat mass and serum levels of insulin and vascular inflammation (Matsabura et al., 2002; Matsuzawa et al., 2004; Fantin et al., 2020; Maeda et al., 2020; Xu et al., 2020; Ouchi N, et al., 2003; Shibata et al., 2011; Piao et al., 2017). Of these adipokines, adiponectin has attracted attention because of its positive corelation with lower risk of cardiometabolic anomalies and prolonged life span in several clinical studies (Achari and Jain 2017; Maeda et al., 2020; Niu et al., 2013). For example, people with long lifespan like centenarians have higher levels of circulating adiponectin (Arai et al., 2011 and 2019). Notably, women have significantly higher levels of adiponectin compared to men, which is associated with increased lifespan, delayed progression of age-related vascular illnesses including endothelial dysfunction, neointimal formation, vascular stiffness and decreased mortality (Costanito et al., 2016; Pischon et al., 2011). Furthermore, multiple genetic animal models showed that specific lacking of adiponectin contribute to vascular senescence, impaired angiogenesis as well as a decline in cardiovascular regeneration capacity (Li et al., 2021; Piao et al., 2018). In contrary to the reports of beneficial roles of adiponectin, increased levels of adiponectin are identified in aged people, a condition commonly known as “adiponectin paradox in the elderly” (Arai et al., 2019; Nagasawa et al., 2018; Kistrop et al., 2005; Francischetti et al., 2020). Notably, greater serum adiponectin levels are also associated with low skeletal muscle density, cognitive impairment, and greater risk of disability and death (Arai et al., 2019; Nagasawa et al., 2018; Kistorp et al., 2005; Francischetti et al., 2020). Hence, further research is needed to determine the context-specific effects of this adipokine on ageing or age-related cardiovascular disease. Serum concentrations of inflammatory adipocytokines, such as leptin and resistin, increase with the age and are positively corelated with the accumulation and redistribution of adipose tissue, vascular inflammation and adversely affects the cardiac performance and vascular health (Fantin et al., 2020; Xu et al., 2020; Unger et al., 2005). In older adults, higher concentrations of leptin and resistin are associated with greater risk of physical frailty, health deterioration and reduced chances of organism’s survival (Rava et al., 2020; Lana et al., 2020; Gencer et al., 2016). Older patients with severe aortic valve disease have higher plasma resistin levels, which are associated with increased inflammatory macrophage content and degree of valvular calcification (Mohty et al., 2010; Sweeney et al., 2021). Furthermore, concomitant with hyperleptinemia, sensitivity to leptin declines in old age, promoting the development of age-related cardiometabolic abnormalities (Gonzalez et al., 2013; Ma et al., 2002; Soderberg et al., 2003). However, the data concerning the relationship between leptin levels and ageing in healthy population are controversial as some clinical studies identified either decrease or no change in leptin levels with age (Isidori et al., 2000; Moller et al., 1998; Zhong et al., 2000). Therefore, understanding the effects of targeting these adipokines in ageing is imperative to design therapies targeting the adipokines. Ageing is associated with deregulation of nutrient-sensing signaling pathways (Harrison et al., 2009; Akbari et al., 2019). Factors like diet, physical exercise and caloric restriction that affect nutrient-sensing signaling pathways have crucial roles in healthy ageing and human longevity (Arai Y et al., 2019; Mercken et al., 2012; Barzilai et al., 2012; Madeo et al., 2019). These anti-ageing habits alter serum adipokines and extend lifespan (Barzilai et al., 2012; Madeo et al., 2019). Caloric restriction mimetics including metformin and resveratrol are known to correct the changes in the VAT that are age associated (Le Pelletier et al., 2021; Zhang et al., 2021). By increasing serum adiponectin levels, the caloric restriction mimetics elicit cardioprotective effects by inhibiting the synthesis of adhesion molecules in endothelial cells and subsequent extravasation of monocytes into the tissue space (Barzilai et al., 2012; Aldhahi et al., 2003). In addition, these mimetics-induced serum adiponectin alterations impeded the progression of atherosclerosis by inhibiting the secretion of pro-inflammatory cytokines like TNF-α from monocyte/macrophages and foam cells in the vasculature (Ahmadi et al., 2011; Fernández-Real et al., 2003; Ouchi et al., 2003). Long-term caloric restricted obese humans have considerably less concentrations of fasting serum glucose and leptin compared to age-and BMI-matched obese individuals (Mitterberger et al., 2010). Physical exercise and caloric restriction reprogram the functions of VAT, reset the adipokine secretion in ageing and improve cardiovascular health.

Summary and future perspectives:

Cardiovascular disease is the leading cause of adult mortality in the United States, imposing a heavy burden on the healthcare system. Obesity and diabetes are common co-morbidities in individuals with CVD. Cardiometabolic basis of CVD is an emerging field, and adipose tissue is considered as a key player affecting cardiac health and CVD. Our understanding of adipose tissue functions has come a long way over the past couple of decades. Studies have established adipose tissue as a key regulator of metabolism in the body via secretion of adipokines. The discovery of VAT as an endocrine organ that secretes adipokines with pro- and anti-inflammatory effects that influence physiology and disease by way of their downstream signaling has opened new areas of investigation in cardiovascular biology and metabolism. Chronic inflammation characterized by increased pro-inflammatory cytokine secretion by adipose tissue mediates adverse systemic effects. Adipokines exert varied effects on CVD – atherosclerosis, hypertension, endothelial biology and cardiac function. While adiponectin and omentin have documented cardioprotective effects to counter inflammation, endothelial dysfunction and cardiac remodeling, leptin and resistin propagate inflammation, atherosclerosis and endothelial dysfunction. However, some adipokines have pro- and anti- inflammatory properties in a context–dependent manner, exerting conflicting actions on metabolism and inflammation. The pathogenesis of cardiovascular dysfunction regulated by adipocytokines is highly complex and poorly understood due to significant knowledge gap. Adiponectin and leptin, the most dominant adipokines, have multifaceted pathological roles afflicting cardiovascular and adipose dysfunctions. Additionally, both adipokines play essential and indispensable roles in maintaining cardiovascular health. Despite the positive association of low levels of adiponectin with increased incidence of obesity-linked CVD, higher circulatory levels of adiponectin do not always confer the protection against CVD. Especially, in patients with low BMI, higher levels of adiponectin are detrimental to their cardiovascular health. Moreover, low plasma levels of leptin are positively associated with adverse CVD outcomes in these patients. Conversely, in patients with higher BMI levels, both elevated leptin and leptin/adiponectin concentrations are accompanied by adverse cardiovascular outcomes. The mechanisms of the context-dependent roles of these adipokines are not known. Hence, understanding the molecular and physiological effects of these adipokines on vasculature and myocardium in CVD patients having various BMI is required to develop novel therapeutics approaches.

Abbreviations:

ABCA1

ATP-binding cassette transporter A1

ABCG1

ATP-binding cassette sub-family G member 1

Adipo R

adiponectin receptor

Akt

protein kinase B

Apo

apolipoprotein

AMPK

5’ adenosine monophosphate-activated protein kinase

BMI

body mass index

CD

cluster of differentiation

CVD

cardiovascular disorders

EC

endothelial cells

eNOS

endothelial nitric oxide synthase

LDL

low density lipoprotein

LV

left ventricle

HF

heart failure

HUVEC

human umbilical vein endothelial cells

JAK / STAT

Janus-activated kinase/signal transducers and activators of transcription

JNK

c-Jun N-terminal kinase

iNOS

inducible nitric oxide synthase

MCP-1

monocyte chemoattractant protein 1

MAPK

mitogen-activated protein kinase

MMP

matrix metalloproteinase

NADPH oxidase

nicotinamide adenine dinucleotide phosphate oxidase

NF-κB

nuclear factor kappa-light-chain-enhancer of activated B cells

NLRP3

NLR family pyrin domain containing 3

oxLDL

oxidized LDL

PI3K

phosphoinositide 3-kinases

PK

protein kinase

PPAR

peroxisome proliferator-activated receptor

ROS

reactive oxygen species

SGK

serum and glucocorticoid-regulated kinase 1 or Serine/threonine-protein kinases

SMC

smooth muscle cells

SR-A

scavenger receptor A

VSMC

vascular smooth muscle cells

VAT

visceral adipose tissue

Biographies

Partha Dutta (left) is an Associate Professor at the University of Pittsburgh, USA. His research interests focus on immunology of cardiovascular disease. His lab is mainly involved in investigating how myeloid cells, such as monocytes and macrophages, induce inflammation in metabolic diseases such as type II diabetes, IR and obesity, and cardiovascular diseases such as heart failure and myocardial infarction. The ultimate goal of the lab is to develop potential therapeutic avenues to check generation of myeloid cells in the bone marrow and spleen, and recruitment of myeloid cells to sites of inflammation such as adipose tissue and the myocardium.

Sathish Babu Vasamsetti (right) is a senior post-doctoral associate at the University of Pittsburgh, USA. His research mainly focuses on investigating the role of myeloid cells, mainly macrophages in disease pathogenesis such as atherosclerosis, myocardial infarction, heart failure, diabetes, obesity and IR. He has identified the importance of adipose-derived cytokines such as adiponectin in the context of myocardial infarction induced IR.