Introduction
Coronary artery disease (CAD) is the leading cause of morbidity and death in the rapidly developing world [1]. Obesity is a worldwide epidemic and independent risk factor for CAD, as it is associated with macrophage accumulation in adipose tissue [2]. Adipose tissue has received much scientific attention because it exerts endocrine function by secreting a large number of bioactive substances as well as adipokines. These adipose tissue derivatives appear to play an important role in energy homeostasis and inflammation [3]. Although adipokine concentrations increase systemically and locally in atherosclerotic lesions, their contribution to atherosclerosis progression has not been fully elucidated [4]. Only a few studies have evaluated the direct relationship between adipokine concentrations and coronary atherosclerosis measurements [5].
Vaspin
Serpin derived from visceral adipose tissue (vaspin), a member of the serine protease inhibitor family, has been found to be predominantly secreted from visceral adipose tissue in the rat model [6]. Accumulated data indicate that vaspin is associated with obesity and glucose metabolism parameters in adults and emphasize its insulin-sensitizing effects [7]. It is assumed that vaspin induction with adipose tissue may provide a compensatory mechanism in response to obesity, severe insulin resistance, and type 2 diabetes mellitus (T2DM). However, the relationship between vaspin and human atherosclerosis is still unclear. Aust et al. [8] reported low circulating vaspin levels in symptomatic and asymptomatic patients with carotid stenosis. Experimental and clinical studies are needed to shed more light on the precise role of vaspin in atherosclerosis. Since there is no review in the literature of this subject, our aim is to understand the effects of changes in serum vaspin levels and their prognostic significance in CAD.
Vaspin is a new biological marker of obesity and impaired insulin sensitivity [9]. Kadoglou et al. [10] showed a negative correlation between serum vaspin levels and angiographically proven CAD for the first time in their study. In addition to the presence of CAD, they found that low vaspin concentrations are correlated with the severity of CAD, expressed by the Gensini score and the number of significantly narrowed coronary arteries. Concerning the inverse relationship between vaspin concentration and cardiovascular events, findings suggest that vaspin is involved in the pathophysiology of coronary atherosclerosis [8]. Although the mechanistic role of vaspin in CAD progression cannot be clarified by this study, it has been hypothesized that vaspin has a suppressive effect on the inflammatory process [10]. Seeger et al. [11] documented a negative relationship between vaspin and C-reactive protein (CRP) in patients receiving long-term hemodialysis. High-sensitivity CRP is a well-documented predictor of cardiovascular disease [12, 13]. Thus, the vaspin-associated inflammatory process appears to be a promising atheroprotective mechanism requiring further investigation [14].
Epicardial adipose tissue is a true visceral adipose tissue that accumulates around the heart and is associated with left ventricular mass and metabolic syndrome [15, 16]. Importantly, epicardial fat is a metabolically active tissue that produces various bioactive molecules that can significantly affect cardiac function [17]. Among these, vaspin has been reported to be consistently expressed in periaortic, pericoronary, and epicardial adipose tissue [18]. Vaspin is an adipokine that is expressed in epicardial adipose tissue and its level is increased in patients with nonalcoholic fatty liver disease (NAFLD) [19].
Discussion of the relationship between vaspin levels and atherosclerosis may be due to different patient populations in these studies or other unspecified factors that may affect vaspin or substrate protease. Increased serum vaspin levels, especially in NAFLD patients, suggest that elevated levels of this adipokine may be a compensatory mechanism for insulin resistance [20]. This may reflect a compensatory arrangement of a potentially useful factor through an incomprehensible mechanism, considering the disadvantageous cardiovascular environment of NAFLD [21, 22]. Therefore, under normal and noninflammatory conditions, higher levels of vaspin can be considered to be truly beneficial as both a marker and a mediator of cardiovascular risk.
However, in a high-risk population with NAFLD, there may be a counterregulation or compensatory increase in vaspin levels. Alternatively, increased concentrations may be a result of resistance at the vaspin receptor level. Thus, in such cases, elevated vaspin levels may be indicative of an underlying insulin resistance condition or vaspin resistance. Fu et al. [23] recently reported that vaspin has no effect on normal human endothelial cells and cannot prevent TNF-induced inflammatory damage.
Vaspin messenger RNA (mRNA) expression in visceral adipose tissue can be barely detected in 6-week-old rats; however, it increases in Otsuka Long-Evans Tokushima fatty rats to the age of 30 weeks (prediabetic state) and then falls (diabetic state). Exercise and treatment with insulin and insulin-sensitizing pioglitazone prevent a diabetes-related decrease in vaspin expression in visceral adipose tissue. Administration of vaspin to obese mice fed a high-fat, high-sucrose diet increases glucose tolerance and insulin sensitivity [24].
Contrary to findings in animal models, plasma vaspin concentration increases paradoxically in humans with a high body mass index (BMI) and has a negative correlation with insulin sensitivity [9]. Plasma vaspin concentration decreases with metformin therapy and increases with exercise training [9]. Recent studies have reported that plasma vaspin concentration is associated with CAD and the presence of diabetic microvascular complications [8, 10, 25].
The finding that serum vaspin concentration is significantly higher in women supports previous studies showing sexual differences in serum vaspin levels [11]. The role of androgens in the sex-specific effect of other adipocytokines such as leptin and adiponectin is very interesting [26, 27]. A study showed that estrogen therapy increased vaspin expression and secretion in omental adipose tissue explants [17]. Choi et al. [28] found that the relationship between vaspin concentration, metabolic syndrome, and coronary artery stenosis was different between men and women. In women, the vaspin concentration was not associated with metabolic syndrome but was significantly associated with the characteristics of coronary artery atherosclerosis; however, the opposite was true in men. Although the characteristics of patients may explain at least some of this inconsistency in studies, the mechanism responsible for this inconsistency is unclear. Compared with men, women with coronary artery stenosis had much worse cardiovascular risk profiles, such as high blood pressure, high BMI, and high triglyceride concentration. This suggests that vaspin levels in women with coronary artery stenosis reflect a severer deterioration of metabolic risk factors [28].
Plasma vaspin concentration is associated with metabolic syndrome and obesity parameters in men. Vaspin concentration was significantly lower in diabetic men with longer-term diabetes or microvascular complications. Vaspin concentration is significantly associated with coronary artery stenosis in women, suggesting that vaspin plays a role in human obesity and atherosclerosis [28]. Kadoglu et al. [29] demonstrated that atorvastatin treatment, rather than lifestyle modification, increased vaspin serum levels in hypercholesterolemic patients at moderate cardiovascular risk. Pleiotropic-related effects of atorvastatin are clinically important; however, the effect of atorvastatin on long-term clinical outcomes has not been established.
Li et al. [30] found a decrease in mRNA expression and vaspin plasma levels in peripheral blood mononuclear cells in a homogeneous group with CAD. Furthermore, low vaspin concentrations and expression were significantly correlated with CAD severity and unstable angina pectoris, and findings suggest that vaspin may serve as a new biomarker in CAD as well as unstable angina pectoris.
Alterations in the vaspin gene may impair its physiological function, and thus this may increase the risk of certain diseases. Indeed, one study found a significant high-risk association between vaspin SNP rs2236242 and T2DM in individuals with the AA genotype [31]. Li et al. [32] investigated four polymorphisms in their study and found that the AA genotype of rs2236242 was associated with CAD in the Chinese population. However, since the frequencies of rs60231678, rs35262691, and rs17094917 in the 5′ untranslated region and promoter of vaspin were not significantly different between individuals with CAD, individuals with diabetes, and control individuals, there was no significant evidence that these polymorphisms had a significant effect on susceptibility to diabetes and CAD in the Chinese population.
Although Germans have rs2236242 associated with diabetes, functional outcomes and effects on disease are not known [31]. Intronic SNPs may have an effect on splicing activity, stability of the transcribed mRNA, and enhancing activity [33]. On the basis of this study, it cannot be concluded that the effect of rs2236242 on the risk of CAD contributes to vaspin mRNA expression or stability, since no significant relationship was observed regarding vaspin mRNA expression or stability [32]. The relationship between rs2236242 and CAD risk may be partly explained by the mechanisms of inflammation, since rs2236242 is closely related to CRP. In patients without CAD, those carrying the TT genotype had the lowest serum CRP concentration among all genotypes. In recent years, it has become clear that a proinflammatory condition contributes to the development of atherosclerosis [34]. Therefore, it is reasonable to predict that a low degree of inflammation will delay the onset of potential CAD in individuals carrying the T allele of rs2236242.
The mechanisms by which vaspin expression is regulated in humans remain unclear. Sex, age, kidney functions, diet, etc. all affect serum vaspin levels [11]. Increased serum vaspin levels are considered as a compensatory factor that triggers obesity and insulin resistance [24]. Studies have revealed increased serum vaspin levels in patients with insulin resistance, such as women with polycystic ovary syndrome [35]. However, it was frequently observed that there is a U-shaped correlation between serum vaspin concentration and BMI [8]. Increased insulin sensitivity with rosiglitazone, metformin, or other drugs decreased serum vaspin levels, while statin increased vaspin levels in hypercholesterolemic patients [29]. Lifestyle modification has been shown to significantly reduce vaspin levels [36], but in some other studies no such effect was observed [37].
Zhang et al. [38] found that plasma vaspin concentration was correlated with the severity of CAD. Furthermore, plasma vaspin may have a pivotal role to avoid unnecessary coronary angiography. Kadoglou et al. [39] demonstrated that vaspin had no prognostic value in patients with acute ischemic stroke. Nakatsuka et al. [40] reported that changes in the vaspin gene were responsible for the compensatory effects of obesity-related metabolic abnormalities. It was shown that vaspin-transgenic mice are protected against diet-induced obesity, glucose tolerance disorders, and fatty liver, whereas mice with vaspin deficiency develop glucose intolerance because of rearrangement of endoplasmic reticulum (ER) stress markers. Vaspin was presented as a circulating serpent that serves as a ligand for a cell surface receptor complex, GRP78/MTJ1, in the liver after plasma and ER stress–mediated translocation [40].
Vaspin implements its anti-inflammatory effect by binding to GPR78, a protein regulated by glucose, and the following signals positively affect metabolic disorders due to ER stress [40]. In another study, Nakatsuka et al. [41] demonstrated that vaspin acts as a ligand for a cell surface GRP78/ strain bound anion channel complex in endothelial cells and therefore exhibits antiapoptotic, proliferative, and protective effects on vascular walls in rat models of streptozotocin-induced diabetes mellitus. These reactions demonstrate the molecular basis of direct correlation between these adipokines and endothelial cells in the presence of obesity and ER stress responses [40, 41]. In addition, vaspin protects endothelial cells with an inhibitory effect on nuclear factor κB [42].
Akyol et al. [43] found low serum vaspin levels in patients undergoing dialysis. In addition, serum vaspin levels were shown to be significantly correlated with glomerular filtration rate and carotid intima-media thickness. The work by Sathyaseelan et al. [44] represents progress in biomedical science because they suggested that low serum vaspin concentration may be an independent variable and a risk factor for acute coronary syndrome in patients with T2DM. These findings may have important implications both for understanding the pathophysiology of acute coronary syndrome and for the development of future therapeutic and coronary prevention approaches.
Stančík et al. [45] demonstrated that plasma vaspin concentration in stable CAD patients probably reflects metabolic compensatory and endothelial replacement processes and varies according to the estimated pretest probability and the presence of significant coronary artery stenosis. Their results suggest that vaspin measurement in CAD patients may be clinically useful in patients with a pretest probability of less than 66%. The evidence they present does not support the use of vaspin measurement as a biochemical marker for CAD diagnosis in the general population.
Motawi et al. [46] found that low serum vaspin levels were associated with coronary artery stenosis in obese Egyptian patients with T2DM, and changes in these adipokine levels suggest that these patients are susceptible to the pathogenesis of coronary artery stenosis. In obese patients with T2DM with CAD, there was a strong positive correlation between vaspin and omentin 1, with cross-interaction. However, the precise molecular mechanism underlying the role of such interaction in CAD needs to be further elucidated. Finally, this study highlights the potential utility of vaspin as a noninvasive biomarker to support the diagnosis of coronary artery stenosis in obese Egyptian patients with T2DM.
Sato et al. [47] demonstrated that vaspin inhibits atherogenesis by suppressing vascular inflammation, macrophage foam cell formation, and vascular smooth muscle cell migration and proliferation. Vaspin also contributes to plaque stabilization by increasing collagen content and decreasing the intraplaque macrophage to vascular smooth muscle cell ratio. The therapeutic goal concerning vaspin is to manage atherosclerosis and related diseases, as well as to maintain vascular health.
Conclusions
Vaspin is a new biological marker of CAD. Low serum vaspin levels are associated with coronary artery stenosis. Plasma vaspin concentration reflects possible endothelial dysfunction in CAD patients and correlates with CAD severity. Plasma vaspin concentration is associated with metabolic syndrome and obesity parameters. The ultimate goal regarding vaspin is to detect and prevent diseases caused by atherosclerosis, as well as to preserve vascular health and contribute to public health. Larger and more extensive cohort studies are needed to determine whether vaspin is a valuable marker in the diagnosis and follow-up of CAD.