Adipsin in the pathogenesis of cardiovascular diseases

Abstract

Adipsin is an adipokine predominantly synthesized in adipose tissues and released into circulation. It is also known as complement factor-D (CFD), acting as the rate-limiting factor in the alternative complement pathway and exerting essential functions on the activation of complement system. The deficiency of CFD in humans is a very rare condition. However, complement overactivation has been implicated in the etiology of numerous disorders, including cardiovascular disease (CVD). Increased circulating level of adipsin has been reported to promote vascular derangements, systemic inflammation, and endothelial dysfunction. Prospective and case-control studies showed that this adipokine is directly associated with all-cause death and rehospitalization in patients with coronary artery disease. Adipsin has also been implicated in pulmonary arterial hypertension, abdominal aortic aneurysm, pre-eclampsia, and type-2 diabetes which is a major risk factor for CVD. Importantly, serum adipsin has been recognized as a unique prognostic marker for assessing cardiovascular diseases. At present, there is paucity of experimental evidence about the precise role of adipsin in the etiology of CVD. However, this mini review provides some insight on the contribution of adipsin in the pathogenesis of CVD and highlights its role on endothelial, smooth muscle and immune cells that mediate cardiovascular functions.

Graphical Abstract

1.0. Introduction

Adipsin, a serine-protease homolog, is an adipokine produced exclusively in adipose tissues and released into circulation (1). The concentration of adipsin in plasma typically ranges from 1 to 2 μg/mL in healthy adults, where it is filtered through the glomerular capillaries, reabsorbed by the renal tubules, and rapidly catabolized within cells. However, its concentration may vary with disease condition involving renal injury, causing approximately a 10-fold increase in adipsin level due to reduced glomerular filtration (2). Adipsin concentrations are not different between healthy men and women (3). While a high adipsin concentration may correlate positively with body weight, a low plasma concentration has been reported in diabetic animals and humans (4). There is no comprehensive study that compares adipsin levels among different ethnic groups. Also, there is paucity of data to support that adipsin concentration varies with genetic polymorphism. Adipsin is also known as complement factor-D (CFD), exerting significant influence on the complement system by acting as a rate-limiting component in the activation of alternative complement pathway (5). Once released into circulation, CFD is rendered inactive by self-inhibitory loop because there is no specific endogenous inhibitor. Thus, a well-coordinated control is crucial to inhibit inappropriate cleavage of the endogenous biomolecules aside its specific substrate. However, this protein is activated during immune suppression of infectious substance (6).

Functionally, adipsin plays a crucial role in the activation of complement system, which represents a major constituent of the innate immunity. This adipokine initiates and amplifies the alternative complement pathway by catalyzing the cleavage of its specific substrate, factor-B, to synthesize complement factor-3. Absence of CFD has been shown to cause inactivity of the alternative pathway (7, 8). Moreover, adipsin contributes to the complement amplification loop that mediates responses from the lectin (LP) and classical complement pathway (CP) activation (9). Human adipsin deficiency is a very rare condition, and patients tend to have normal phenotype but prone to infection due to reduced CFD level and defective alternative pathway activation (10).

Adipsin may also exert detrimental effects on cardiovascular function. Numerous experimental evidences have shown that complement system activation enhances leukocyte accumulation in extracellular matrix (ECM), facilitates endothelial cell (EC) activation, stimulates pro-inflammatory mediators from smooth muscle cells thereby promoting cardiovascular derangements (11, 12). Interestingly, increased adipsin concentration correlates positively with all-cause death, rehospitalization, incidences of myocardial infarction and has been recognized as a unique prognostic marker in coronary artery disease (13). Also, increased circulating adipsin is directly associated with increased carotid intima-media thickness (CIMT) and metabolic disturbances (14). In this mini review, we search through literatures to provide insight on the contributions of adipsin in the pathogenesis of cardiovascular diseases, especially its roles on endothelial, smooth muscle and immune cells that significantly impact the cardiovascular system.

2.0. Adipsin in alternative pathway and complement system activation in cardiovascular diseases.

The alternative pathway is constantly active due to self-activation, and it plays a critical role in complement response amplification independent of the classic pathway as well as maintaining low-level activity of the complement system (15). CFD regulates complement system by promoting the activation of alternative pathway (AP). Studies have shown that CFD is a protease specific to the AP and that a small amount of CFD is sufficient to elicit an appreciable time-dependent increase in AP activity (16). On the other hand, studies using animal models have shown that CFD deficient mice with lipodystrophy exhibit a reduced AP activity, while antibody to CFD suppress AP activation without affecting the classical pathway (17).

CFD functions not only as the rate-limiting protease in the production of C3 convertase required for the AP activation, but also is important in the proliferation of complement system through the amplification loop of the AP (Figure 1). Although selective inhibition of the AP by CFD inhibitor results in significant inhibition of CP-mediated terminal complement activation (9), both the CP and LP uses the AP amplification loop to elicit their responses. Thus, CFD can eventually amplify the output of all the three pathways via a positive feedback mechanism due to the enhanced production of C3-convertase required for the breakdown of complement factor-5, a major effector protein in the complement system, with resultant production of C5a (anaphylatoxin) and C5b, a membrane attack complex that destroys pathogens and promotes cell lysis (18, 19). Amplification of the complement pathways is associated with continuous production of C3a and C5a that trigger more cleavage of proteolytic enzymes as well as other cellular biomolecules, which promote inflammation as well as immune cell and phagocyte infiltration that further cause activation of the complement system (20, 21), consequently contributing to cardiovascular diseases.

Fig. 1.

Overview of the complement system activated by the classical, lectin and alternative pathways. Factor-D (FD) acts as an important protease in AP activation resulting in the generation of C3 convertase (C3bBb) that cleaves C3 into C3a (anaphylatoxin) and C3b. Also. FD contributes significantly to AP amplification, in which multiple C3s are cleaved into C3b to produce extra C3 convertase (C3bBb) to generate even more C3 that is utilized by the CP and LP to elicit their responses. This strong amplification loop leads to full complement system activation. C3b attaches to the membrane-bound C3bBb complex to produce C5 convertase (C3bBb3b) that cleaves C5 into C5a (anaphylatoxin) and C5b, which assemble membrane attack complex (MAC) and further disrupt and lyse pathogens.

The CODAM study conducted by Hertle, Arts (22) shows that the AP can be spontaneously activated in blood vessels and is associated with cardiovascular derangements. The AP can also be activated and dysregulated without terminal complement activation in patients with heart failure, owing to an increased level of CFD (23, 24). In addition, the complement system promotes the formation of atherosclerotic plaques, which narrows the vascular lumen and causes ischemia or rupture with resultant thrombosis that enhances the development of acute coronary disease (25, 26).

3.0. Adipsin and cardiovascular diseases: insight from epidemiological studies

The circulating level of Adipsin has been correlated with the incidence of CVD, making this protease an important biomarker for assessing CVD and potential therapeutic target in this disorder. Ohtsuki, Satoh (13) have shown that Adipsin is a novel biomarker in the diagnosis of coronary artery disease (CAD) and significantly associated with all-cause death and rehospitalization in these patients. An increased level of adipsin is reported in adults with growth hormone deficiency complicated with dysfunctional glucolipid metabolism (27). Abnormal lipid metabolism is a significant risk factor for CAD, suggesting that adipsin can be an early biomarker of CVD. Coronary angiography assessment using optical coherence tomography suggests that serum adipsin is an accurate biomarker for evaluating thin-cap fibroatheroma (TCFA), and this protease is positively associated with plaque vulnerability in patients with CAD (28).

Transcriptomic analyses indicate that an increased expression of adipsin in systemic sclerosis is associated with pulmonary arterial hypertension (PAH) (29). EC Fli1 (Friend leukemia virus integration 1) deficiency partially upregulates adipsin expression and contributes to the development of PAH (30). A predominant increase in C3a and CFD has been reported in the human right ventricle, and CFD deficiency in animal model of pulmonary artery constriction (PAC) reduces right ventricular remodeling and fibrosis, while pharmacological inhibition of C3a receptor significantly improves right ventricular function (31). Additionally, an increased circulating adipsin level positively correlates with increased carotid intima-media thickness (14). In patients with polycystic ovarian syndrome (PCOS), the increased level of circulating adipsin is positively associated with body mass index (BMI) and insulin resistance and is an independent predictor of carotid intima-media thickness (14). Moreover, the increased plasma and urine level of adipsin in healthy pregnant women at the third trimester is hypothesized to be an important indicator of preeclampsia, a pathological condition characterized by increased blood pressure (32, 33).

Adipsin promotes vascular endothelial dysfunction by activating the AP and thus increasing the production of complement proteins such as C3a and C5a (34, 35), which justifies the potential to use circulating adipsin level as a novel biomarker for CVD. Activation of the AP is longitudinally correlated with negative cardiovascular outcomes, such as ischemia and infarction (22). Population-based cohort study shows significant correlation of adipsin and complement protein-3 (C3) with arterial stiffness although it is related to type-2 diabetes and metabolic dysfunctions Jin, Reesink (36).

4.0. Adipsin in cardiovascular disease: insight from experimental studies

Adipose tissues, especially the epicardial and perivascular adipose tissues (PVAT) surrounding the heart and blood vessels, have significant influence on the vascular system due to their anatomical location as well as synthesis and release of adipokines including adipsin into the circulation (37, 38). These adipokines mediate vascular remodeling, compromise EC integrity, promote smooth muscle cell phenotypic switch, oxidative stress, macrophage infiltration and cellular inflammation that contribute to the pathogenesis of cardiovascular dysfunctions (39, 40).

Adipose tissue-derived adipsin promotes risk factors associated with CVD. Genomic analyses of epicardial adipose tissue in patients with atrial fibrillation show that adipsin is abundantly expressed in this tissue (41), which could be responsible for the involvement of epicardial adipose tissue (EAT) in cardiac diseases (42, 43). A recent study finds that EAT-derived adipsin exacerbates cardiovascular injury by promoting cardiomyocyte death following myocardial infarction (44). An increased adipsin level activates Poly ADP-ribosepolymerase-1 (PARP-1) activity, which depletes NAD level with resultant decrease in Sir2alpha deacetylase activity in cardiomyocytes. However, another study shows that adipsin mediates iron homeostasis by upregulating ferritin heavy chain (FTH) and downregulating transferrin receptor (TFRC) to mitigate cardiac remodeling after myocardial infarction (45). In this study, both co-immunoprecipitation assay and immunofluorescence staining show a significant interaction and colocalization of adipsin with iron homeostasis related protein-2 (IRP2) in an in-vitro hypoxia model. Thus, IRP2, an important regulator of iron homeostasis, is proposed as a downstream mediator for the cardioprotective effect by adipsin. On the other hand, Shahini, Michelsen (24) have reported that an increase in adipsin level exacerbates systemic inflammation, cardiac dysfunction (especially worsen diastolic function), and neurohormonal deterioration in patients with chronic heart failure. Despite the conflicting reports from recent studies, the mechanistic role of adipsin in the pathogenesis of cardiovascular disease needs to be further explored, especially the roles of cellular mediators (such as endothelial, smooth muscle, and immune cells) in cardiac functions.

4.1. Effect of adipsin on ECs

Vascular ECs mediate the complex interplay between plasma and vascular tissue, especially the VSMCs, thereby maintaining VSMC contractile phenotype and enhancing optimal vascular functions (such as vascular tone) vital to cardiovascular health (46, 47). Studies have shown that complement activation can increase the expression of inflammatory cytokines and promote immune cell attachment to ECs via chemotaxis, which further inhibits endothelial nitric oxide production and initiate or exacerbate vascular dysfunction (12, 48). This implies that adipsin may be involved in endothelial damage with resultant cardiovascular dysfunction, including PAH.

Recently, Jin, Eussen (49) conducted the Maastricht study involving 2947 participants and reported that circulating adipsin is significantly associated with endothelial dysfunction and low-grade inflammation, which contribute to the progression of cardiovascular injury. In addition, studies elucidating the interplay between obesity and vascular function show that the increased circulating adipsin significantly reduces endothelium-induced vasodilation and exacerbates endothelin-1-dependent vasoconstriction in humans, suggesting that adipsin may aggravate cardiovascular derangement by compromising endothelial functions (50).

Structural analyses show that the endothelium is endowed with complement inhibitory proteins such as Decay accelerating factors (DAF) and other membrane-bound inhibitors including membrane cofactor protein CD46 that helps prevent the interaction between excessive complement activation in the circulation and VSMCs (51). Importantly, theses membrane-bound inhibitors protect endothelium against constant low level AP activation mediated by adipsin (52), suggesting that adipsin may aggravate complement-mediated vascular injury by promoting the AP activation.

4.2. Effect of Adipsin on VSMCs

The medial layer of the blood vessel wall is comprised mainly of VSMCs that control vascular tone and blood pressure. VSMCs can modify their functions and morphology in relation to different stimuli, allowing mature VSMCs to change from a contractile to a synthetic state, a phenomenon known as “phenotype modulation”. This phenotypic modulation contributes to the etiology of several cardiovascular dysfunctions (53). Although, there is a lack of literature on the direct role of adipsin on VSMC phenotype switch, its downstream C3 protein has been reported to exert significant effect on VSMCs phenotype. PVAT-derived C3 due to the abundance of adipsin in this tissue promotes differentiation and migration of adventitial fibroblasts by activating c-Jun N-terminal kinase pathway, thereby contributing to adventitial remodeling and myofibroblast aggregation (54). The adventitial fibroblasts can migrate into the medial layer to induce VSMC phenotype switch via TGF-β1 pathway, promoting revascularization (55, 56). Notably, C3 directly increases synthetic phenotype, promotes VSMC growth, as well as mediates the increased neointimal formation caused by C-reactive protein in spontaneously hypertensive rats and mouse carotid wire injury model (57, 58). Furthermore, increased serum level of adipsin is observed in patients with abdominal aortic aneurysm, suggesting that adipsin may promote VSMC phenotypic modulation during the aneurysm development (59).

4.3. Effect of Adipsin on immune cells

Although the immune system functions as an inherent defense against infection or injury, immune cell (especially T-cells and macrophages) activation has been implicated as a pathogenic mediator of cardiovascular diseases. These cells are often recruited from circulation into vascular beds by activated ECs and later differentiated into unique effector cells that contribute to the development of CVD (60, 61).

Macrophages participate in dynamic interactions among different vascular cells and mediate VSMC phenotype modulation (62). Evaluation of the interaction between macrophages and adipocytes shows that both cells express adipsin that promotes preadipocyte differentiation into macrophages (63). Adipsin deficiency inhibits the recruitment of monocytes, neutrophils, and macrophages into the synovial fluid in serum-injected K/BxN mouse model of inflammatory arthritis (64). In addition, a reduction in atherosclerotic plaque area and macrophage accumulation is reported in ApoE^−/−/AdipsinTg mice after high fat diet feeding for 3 months. Furthermore, adipsin overexpression in oxLDL-stimulated macrophages attenuates lipid uptake by inhibiting CD36/PPARγ levels (65), implicating that adipsin is a unique CVD risk factor. These experimental studies suggest that adipsin may either modulate or enhance macrophage phenotype or function in a disease-dependent manner.

T-cells may infiltrate into myocardium or heart valves to compromise cardiac function with resultant scarring (66). Various cytokines such as leptin, visfatin, adiponectin, resistin from adipose tissues may regulate T-cell activation and differentiation (67). DAF-deficiency in mice activates complement proteins with subsequent amplification of T-cell activity. This enhanced T-cell activity is associated with the AP activation in T-cells, which further promotes the production of local anaphylatoxin (68, 69). Although there is paucity of data on the direct contribution of adipsin to T-cell polarization, literatures have shown that adipsin may influence complement system activation implicated in T-cell immunity. Thus, adipsin may enhance T-cell polarization in the myocardium indirectly, which further regulates cardiac remodeling and the progression of CVD.

5.0. Conclusion

Adipose tissues synthesize and release adipokines, including adipsin, into the circulation, which contributes to the pathogenesis of CVD. Although the correlation between adipsin and CVD, such as coronary artery disease, heart failure, pulmonary arterial hypertension, and pre-eclampsia, has been well documented, the precise mechanisms underlying adipsin functions in the pathogenesis of CVD are yet to be determined. Thus, comprehensive studies using in vitro and in vivo experimental paradigms are needed to explore the specific contributions of this adipokine to the development/progression of CVD, especially its effects on cellular mediators, i.e., immune cells, VSMCs, and ECs (Figure 2).

Fig. 2.

Schematic effect of adipsin on cellular mediators of cardiovascular diseases.

6.0. Future perspective

Insights from epidemiological and experimental studies have shown that adipsin contributes to the development and progression of CVD. However, future research should be geared toward unraveling the underlying mechanisms by which this adipokine promotes cellular derangement associated with CVD. Basic and clinical researchers may employ different approaches, such as genetic modifications or pharmacological interventions with adipsin agonists or antagonists, to evaluate the specific roles of adipsin in these disorders. The results from these studies will help address the paucity of information regarding any confounding variables such as lifestyle, gender, age, and comorbidities that may influence the roles of adipsin in the etiology of CVD. While some adipokines, like adiponectin, omentin, and apelin, exert anti-inflammatory and cardioprotective effects (70, 71), others adipokines, such as visfatin, leptin, resistin, and lipocalin-2, promote inflammation, insulin resistance, EC dysfunction and VSMC apoptosis (72–74). Notably, adipsin may compromise EC function, promote neointimal formation and recruit immune cells into different vascular beds in the setting of CVD. Thus, there may be interplays between adipsin and other adipokines in the development of CVD, which could also be an important subject for future inquiry. Although increased adipsin level has been identified as a unique biomarker in patients with coronary artery disease, atherosclerosis, and correlates positively with ischemic events (13, 75), the combination of adipsin with other biomarkers such as brain natriuretic peptide (BNP) or high-sensitive C-reactive protein (hs-CRP) may be a more valuable diagnostic tool, likely better than adipsin alone, and thus may improve the clinical practice for diagnosing CVD. Furthermore, pharmacological interventions targeting circulating adipsin may inhibit the activation of complement system and further improve management of risk factors associated with CVD. Therefore, unravelling the detailed contributions of adipsin in the etiology of CVD remain an active area of research, which is crucial for revealing the complex interplays between adipsin and other adipokines and addressing confounding variables. The outcomes of these studies could lead to significant discoveries of the therapeutic and diagnostic values of adipsin in the clinical management of CVD.

Abbreviations

CFD

Complement factor-D

ECM

extracellular matrix

CIMT

carotid intima-media thickness

AP

Alternative pathway

CP

Classical pathway

LP

Lectin pathway

FD

Factor D

C3

Complement factor-3

C5

Complement factor-5

MASPs

Manna-binding lectin-associated serine protease

CVD

Cardiovascular disease

CAD

coronary artery disease

PVAT

Perivascular adipose tissue

EAT

Epicardial adipose tissue

VSMC

Vascular smooth muscle cell

ECs

Endothelial cells

TGF-β1

Transforming Growth factor-beta1

ApoE

Apolipoprotein-E

OxLDL

Oxidized low-density lipoprotein

CD36

Cluster of Differentiation 36

PPARγ

Peroxisome Proliferated activated receptor-γ

DAF

Decay accelerating factor