Adipokines and the cardiovascular system: mechanisms mediating health and disease

This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.     

Adiponectin and adipocyte fatty acid binding protein in the pathogenesis of cardiovascular disease

The heart and blood vessels are surrounded by epicardial and perivascular adipose tissues, respectively, which play important roles in maintaining cardiovascular homeostasis by secreting a number of biologically active molecules, termed "adipokines." Many of these adipokines function as an important component of the 'adipo-cardiovascular axis' mediating the cross talk between adipose tissues, the heart, and the vasculature. On the one hand, most adipokines [including tumor necrosis factor-α, resistin, adipocyte fatty acid binding protein (A-FABP), and lipocalin-2] are proinflammatory and causally associated with endothelial and cardiac dysfunction by their endocrine/paracrine actions. On the other hand, adiponectin is one of the few adipokines that possesses multiple salutary effects on the prevention of cardiovascular disease, because of its pleiotropic actions on the heart and the blood vessels. The discordant production of adipokines in dysfunctional adipose tissue is a key contributor to obesity-related cardiovascular disease. This review provides an update in understanding the roles of adipokines in the pathogenesis of cardiovascular disorders associated with obesity and diabetes and focuses on the two most abundant adipokines, adiponectin and A-FABP. Indeed, data from both animal studies and clinical investigations imply that these two adipokines are prognostic biomarkers for cardiovascular disease and even promising therapeutic targets for its treatment.     

Adiponectin and cardiovascular disease: state of the art?

The cardiometabolic syndrome, associated with increased cardiovascular disease risk in the industrialized world, is estimated to affect one in four adults. Although the mechanisms linking obesity and cardiovascular disease remain unclear, research continues to unravel the molecular pathways behind this pandemic. Adipose tissue has emerged as a metabolically active participant in mediating vascular complications, serving as an active endocrine and paracrine organ secreting adipokines, which participate in diverse metabolic processes. Among these adipokines is adiponectin, which seems to possess antiatherogenic and anti-inflammatory effects and may be protective against cardiovascular disease development. The current review describes the pathophysiology of adiponectin in atherosclerotic disease.     

Instigation of endothelial Nlrp3 inflammasome by adipokine visfatin promotes inter‐endothelial junction disruption: role of HMGB1

Recent studies have indicated that the inflammasome plays a critical role in the pathogenesis of vascular diseases. However, the pathological relevance of this inflammasome activation, particularly in vascular cells, remains largely unknown. Here, we investigated the role of endothelial (Nucleotide‐binding Oligomerization Domain) NOD‐like receptor family pyrin domain containing three (Nlrp3) inflammasomes in modulating inter‐endothelial junction proteins, which are associated with endothelial barrier dysfunction, an early onset of obesity‐associated endothelial injury. Our findings demonstrate that the activation of Nlrp3 inflammasome by visfatin markedly decreased the expression of inter‐endothelial junction proteins including tight junction proteins ZO‐1, ZO‐2 and occludin, and adherens junction protein VE‐cadherin in cultured mouse vascular endothelial (VE) cell monolayers. Such visfatin‐induced down‐regulation of junction proteins in endothelial cells was attributed to high mobility group box protein 1 (HMGB1) release derived from endothelial inflammasome‐dependent caspase‐1 activity. Similarly, in the coronary arteries of wild‐type mice, high‐fat diet (HFD) treatment caused a down‐regulation of inter‐endothelial junction proteins ZO‐1, ZO‐2, occludin and VE‐cadherin, which was accompanied with enhanced inflammasome activation and HMGB1 expression in the endothelium as well as transmigration of CD43⁺ T cells into the coronary arterial wall. In contrast, all these HFD‐induced alterations in coronary arteries were prevented in mice with Nlrp3 gene deletion. Taken together, these data strongly suggest that the activation of endothelial Nlrp3 inflammasomes as a result of the increased actions of injurious adipokines such as visfatin produces HMGB1, which act in paracrine or autocrine fashion to disrupt inter‐endothelial junctions and increase paracellular permeability of the endothelium contributing to the early onset of endothelial injury during metabolic disorders such as obesity or high‐fat/cholesterol diet.     

Inflammation and metabolic dysfunction: links to cardiovascular diseases

Abdominal obesity is a major risk factor for cardiovascular disease, and recent studies highlight a key role of adipose tissue dysfunction, inflammation, and aberrant adipokine release in this process. An increased demand for lipid storage results in both hyperplasia and hypertrophy, finally leading to chronic inflammation, hypoxia, and a phenotypic change of the cellular components of adipose tissue, collectively leading to a substantially altered secretory output of adipose tissue. In this review we have assessed the adipo-vascular axis, and an overview of adipokines associated with cardiovascular disease is provided. This resulted in a first list of more than 30 adipokines. A deeper analysis only considered adipokines that have been reported to impact on inflammation and NF-κB activation in the vasculature. Out of these, the most prominent link to cardiovascular disease was found for leptin, TNF-α, adipocyte fatty acid-binding protein, interleukins, and several novel adipokines such as lipocalin-2 and pigment epithelium-derived factor. Future work will need to address the potential role of these molecules as biomarkers and/or drug targets.     

脂肪因子与代谢综合征关系的研究进展

代谢综合症是一系列代谢和心血管功能失调的临床特征,包括中心性肥胖、高血压、血脂异常、高血糖及胰岛素抵抗等,其发病机制及如何预防及控制代谢综合症正日益成为目前的学术热点。目前已经公认,脂肪不仅是能量存储器官,也是一个重要的内分泌器官。脂肪组织分泌的生物活性分子被称为脂肪因子。近年来的研究表明,脂肪因子广泛参与肥胖、2型糖尿病、高血压病及心血管疾病等一系列代谢相关性疾病的病理生理过程。脂肪因子能通过介导一系列的信号转导通路,并广泛参与机体复杂的代谢平衡网络的调节。脂肪因子的失衡能导致机体发生对胰岛素敏感性改变等一系列的生物学反应,从而在肥胖和代谢综合症的病理过程中发挥重要的作用。本文综述了脂肪因子与代谢综合征的关系的研究进展。     

Adipokines oversecreted by omental adipose tissue in human obesity

Central-omental obesity plays a causative role in the pathogenesis of the metabolic syndrome. Adipokines are involved in the pathogenesis of this syndrome. However, adipokines secreted by omental adipose tissue (OAT) are still poorly characterized in human obesity. Therefore, we searched for novel adipokines abnormally secreted by OAT in obesity and examined their relationships with some features of metabolic syndrome and the respective contribution of adipocytes vs. stromal-vascular cells. OAT from obese and nonobese men was fractionated into adipocytes and SV cells, which were then cultured. Medium was screened by medium-scale protein arrays and ELISAs. Adipokine mRNA levels were measured by real-time RT-qPCR. We detected 16 cytokines secreted by each cellular fraction of lean and obese subjects. Of the 16 cytokines, six adipokines were newly identified as secretory products of OAT, which were dysregulated in obesity: three chemokines (growth-related oncogen factor, RANTES, macrophage inflammatory protein-1beta), one interleukin (IL-7), one tissue inhibitor of metalloproteinases (TIMP-1), and one growth factor (thrombopoietin). Their secretion and expression were enhanced in obesity, with a relatively similar contribution of the two fractions. The higher proportion of macrophages and endothelial cells in obesity may contribute to this enhanced production as well as changes in intrinsic properties of hypertrophied adipocytes. Accordingly, mRNA concentrations of most of these adipokines increased during adipocyte differentiation. Eventually, expression of the investigated adipokines did correlate with several features of the metabolic syndrome. In conclusion, six adipokines were newly identified as oversecreted by OAT in obesity. These adipokines may link obesity to its cardiovascular or metabolic comorbidities.     

Identification and validation of novel adipokines released from primary human adipocytes

Adipose tissue is a major endocrine organ, releasing signaling and mediator proteins, termed adipokines, via which adipose tissue communicates with other organs. Expansion of adipose tissue in obesity alters adipokine secretion, which may contribute to the development of metabolic diseases. Although recent profiling studies have identified numerous adipokines, the amount of overlap from these studies indicates that the adipokinome is still incompletely characterized. Therefore, we conducted a complementary protein profiling on concentrated conditioned medium derived from primary human adipocytes. SDS-PAGE/liquid chromatography-electrospray ionization tandem MS and two-dimensional SDS-PAGE/matrix-assisted laser desorption ionization/time of flight MS identified 347 proteins, 263 of which were predicted to be secreted. Fourty-four proteins were identified as novel adipokines. Furthermore, we validated the regulation and release of selected adipokines in primary human adipocytes and in serum and adipose tissue biopsies from morbidly obese patients and normal-weight controls. Validation experiments conducted for complement factor H, αB-crystallin, cartilage intermediate-layer protein, and heme oxygenase-1 show that the release and expression of these factors in adipocytes is regulated by differentiation and stimuli, which affect insulin sensitivity, as well as by obesity. Heme oxygenase-1 especially reveals to be a novel adipokine of interest. In vivo, circulating levels and adipose tissue expression of heme oxygenase-1 are significantly increased in obese subjects compared with lean controls. Collectively, our profiling study of the human adipokinome expands the list of adipokines and further highlights the pivotal role of adipokines in the regulation of multiple biological processes within adipose tissue and their potential dysregulation in obesity.     

Endothelial dysfunction and diabetes: roles of hyperglycemia,impaired insulin signaling and obesity

Endothelial dysfunction comprises a number of functional alterations in the vascular endothelium that are associated with diabetes and cardiovascular disease, including changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. Hyperglycemia is a characteristic feature of type 1 and type 2 diabetes and plays a pivotal role in diabetes-associated microvascular complications. Although hyperglycemia also contributes to the occurrence and progression of macrovascular disease (the major cause of death in type 2 diabetes), other factors such as dyslipidemia, hyperinsulinemia, and adipose-tissue-derived factors play a more dominant role. A mutual interaction between these factors and endothelial dysfunction occurs during the progression of the disease. We pay special attention to the possible involvement of endoplasmic reticulum stress (ER stress) and the role of obesity and adipose-derived adipokines as contributors to endothelial dysfunction in type 2 diabetes. The close interaction of adipocytes of perivascular adipose tissue with arteries and arterioles facilitates the exposure of their endothelial cells to adipokines, particularly if inflammation activates the adipose tissue and thus affects vasoregulation and capillary recruitment in skeletal muscle. Hence, an initial dysfunction of endothelial cells underlies metabolic and vascular alterations that contribute to the development of type 2 diabetes. E.C. Eringa is supported by the Dutch Diabetes Foundation (grant 2003.00.030), the Dutch Kidney foundation (grant C03.2046), and the Dutch organization for scientific research (grant 916.76.179). V.W.M. van Hinsbergh is supported by the European Vascular Genomics Network (grant LSHM-CT-2003–503254).     

Type 2 diabetes and cardiovascular disease: getting to the fat of the matter

The increasing national prevalence of obesity is a major public health concern and a substantial burden on the health care resources of Canada. In addition to the direct health impact of obesity, this condition is a well-established risk factor for the development of various prevalent comorbidities including type 2 diabetes, hypertension, and cardiovascular disease. Historically, adipose tissue has been regarded primarily as an organ for energy storage. However, the discovery of leptin in the mid 1990's revolutionized our understanding of this tissue and has focused attention on the endocrine function of adipose tissue as a source of secreted bioactive peptides. These compounds, collectively termed adipokines, regulate a number of biological functions including appetite and energy balance, insulin sensitivity, lipid metabolism, blood pressure, and inflammation. The physiological importance of adipokines has led to the hypothesis that changes in the synthesis and secretion of these compounds in the obese are a causative factor contributing to the development of obesity and obesity-related diseases in these individuals. Following from this it has been proposed that pharmacologic manipulation of adipokine levels may provide novel effective therapeutic strategies to treat and prevent obesity, type 2 diabetes, and cardiovascular disease.     

The potential of adipokines as therapeutic agents for cardiovascular disease

Adipose tissue functions as an endocrine organ by producing bioactive secretory proteins, also known as adipokines, that can directly act on nearby or remote organs. Most of the adipokines are upregulated by obese conditions, and typically promote obese complications. In contrast, some adipokines, such as adiponectin, CTRP9 and omentin, are downregulated in obese states. These factors exert salutary actions on obesity-linked cardiovascular disorders. In this review, we focus on the significance of adiponectin, CTRP9 and omentin as therapeutic agents for cardiovascular disease.     

Adiponectin: Anti-inflammatory and cardioprotective effects

Adipose tissue is an endocrine organ that plays an essential role in regulating several metabolic functions through the secretion of biological mediators called "adipokines". Dysregulation of adipokines plays a crucial role in obesity-related diseases. Adiponectin (APN) is the most abundant adipokine accounting for the 0.01% of total serum protein, and is involved in a wide variety of physiological processes including energy metabolism, inflammation, and vascular physiology. APN plasma levels are reduced in individuals with obesity, type 2 diabetes and coronary artery disease, all traits with low-grade chronic inflammation. It is has been suggested that the absence of APN anti-inflammatory effects may be a contributing factor to this inflammation. APN inhibits the expression of tumor necrosis factor-α-induced endothelial adhesion molecules, macrophage-to-foam cell transformation, tumor necrosis factor-α expression in macrophages and adipose tissue, and smooth muscle cell proliferation. It also has anti-apoptotic and anti-oxidant effects, which play a role in its cardioprotective action. This review will focus on APN as an anti-inflammatory, anti-atherogenic and cardioprotective plasma protein.     

The double role of epicardial adipose tissue as pro- and anti-inflammatory organ.

Obesity is associated with low grade inflammation. Whether this is just an adaptive response to excess adiposity to maintain a normal oxygen supply or a chronic activation of the innate immune system is still unknown. Recent research has focused on the origin of the inflammatory markers in obesity and the extent to which adipose tissue has a direct effect. The production of adipokines by visceral adipose tissue is of particular interest since their local secretion by visceral fat depots may provide a novel mechanistic link between obesity and the associated vascular complications. Growing evidences suggest that the epicardial adipose tissue, the visceral fat depot located around the heart, may locally interact with myocardium and coronary arteries. Epicardial fat is a source of adiponectin and adrenomedullin, adipokines with anti-inflammatory properties, and several proinflammatory cytokines as well as Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin 1 (IL1), IL-1 h, Interleukin (IL6), Monocyte Chemoattractive Protein-1 (MCP-1), Nerve Growth Factor (NGF), resistin, Plasminogen Activator Inhibitor-1 (PAI-1), and free fatty acids. Epicardial adipose tissue could locally modulate the heart and vasculature, through paracrine secretion of pro- and anti-inflammatory cytokines, thereby playing a possible role in the adiposity-related inflammation and atherosclerosis. On the other hand, epicardial fat could exert a protective effect through adiponectin and adrenomedullin secretion as response to local or systemic metabolic or mechanical insults. Future studies will continue to provide new and fascinating insights into the double role of epicardial adipose tissue in the development of cardiovascular pathology and/or in protecting the heart and arteries.     

AMP-activated protein kinase is a key regulator of obesity-associated factors

An imbalance between caloric intake and energy expenditure leads to obesity. Obesity is an important risk factor for the development of several metabolic diseases including insulin resistance, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. So, controlling obesity could be effective in the improvement of obesity-related diseases. Various factors are involved in obesity, such as AMP-activated protein kinases (AMPK), silent information regulators, inflammatory mediators, oxidative stress parameters, gastrointestinal hormones, adipokines, angiopoietin-like proteins, and microRNAs. These factors play an important role in obesity by controlling fat metabolism, energy homeostasis, food intake, and insulin sensitivity. AMPK is a heterotrimeric serine/threonine protein kinase known as a fuel-sensing enzyme. The central role of AMPK in obesity makes it an attractive molecule to target obesity and related metabolic diseases. In this review, the critical role of AMPK in obesity and the interplay between AMPK and obesity-associated factors were elaborated.     

Role of adipokines in the obesity-inflammation relationship: the effect of fat removal

During the past 10 years, there has been a dramatic increase in the prevalence of obesity in the United States and other developed nations. Recent studies indicate that adipose tissue is an endocrine organ producing numerous proteins, collectively referred to as adipokines, with broad biological activity, that play an important autocrine role in obesity-associated complications. Adipose tissue in general and visceral fat in particular are thought to be key regulators of inflammation. Inflammation is heavily involved in the onset and development of atherothrombotic disease. Moreover, chronic inflammation may also represent a triggering factor in the origin of the metabolic syndrome and type 2 diabetes mellitus. According to a hypothesis, stimuli such as overnutrition, physical inactivity, and aging would result in cytokine hypersecretion and eventually lead to insulin resistance and diabetes in genetically or metabolically predisposed individuals. This article discusses the current understanding of important adipokines thought to be involved in the metabolic and cardiovascular risk associated with obesity. Available evidence linking fat removal by liposuction to modification of cardiovascular risk and vascular inflammatory markers in the obese patient is also presented. Most studies have shown that liposuction produces beneficial effects on insulin resistance and vascular inflammation in the obese patient, reducing its cardiovascular risk. Besides having a significant role in body contouring of the obese patient at the end of the lengthy process of bariatric surgery and massive weight loss, plastic surgery should be incorporated into a multifaceted program of lifestyle changes that allows the obese patient to obtain weight loss and, more importantly, to maintain the reduced weight in the long term.     

Secretome analysis of rat adipose tissues shows location-specific roles for each depot type

Obesity prevalence is reaching pandemic proportions becoming a major public health threat for many industrialized nations. It is especially worrying as it causes a higher risk of premature death due to associated diseases such as type 2 diabetes, cardiovascular disease, and some cancers. Current evidence shows biological and genetic differences between adipose tissues depending on its anatomical location. Particularly, upper body/visceral fat distribution in obesity is closely linked to metabolic complications. In this report, we characterize for the first time the secretome of rat adipose tissue explants from different anatomical localizations and its differential analysis. Visceral, subcutaneous, and gonadal fat specific secretomes and differentially secreted proteins among the three fat depots were analyzed by 2-DE and MS. Reference maps for location-specific adipose tissue secretomes are shown and the 45 most significant differences are listed. Identified proteins include classical adipokines and novel secreted proteins. Interestingly, our results show that the type of proteins and their role in different biological processes diverge significantly when comparing the set of proteins identified from visceral, subcutaneous and gonadal fat explants. This study emphasizes and supports the differential role of adipose tissue in accordance to its anatomical localization.     

Hypoxia and the endocrine and signalling role of white adipose tissue

White adipose tissue is a major endocrine and signalling organ. It secretes multiple protein hormones and factors, termed adipokines (such as adiponectin, leptin, IL-6, MCP-1, TNFalpha) which engage in extensive cross-talk within adipose tissue and with other tissues. Many adipokines are linked to inflammation and immunity and these include cytokines, chemokines and acute phase proteins. In obesity, adipose tissue exhibits a major inflammatory response with increased production of inflammation-related adipokines. It has been proposed that hypoxia may underlie the inflammatory response in adipose tissue and evidence that the tissue is hypoxic in obesity has been obtained in animal models. Cell culture studies have demonstrated that the expression and secretion of key adipokines, including leptin, IL-6 and VEGF, are stimulated by hypoxia, while adiponectin (with an anti-inflammatory action) production falls. Hypoxia also stimulates glucose transport by adipocytes and may have a pervasive effect on cell function within adipose tissue.     

Early experimental obesity is associated with coronary endothelial dysfunction and oxidative stress

Obesity is independently associated with increased cardiovascular risk. However, since established obesity clusters with various cardiovascular risk factors, configuring the metabolic syndrome, the early effects of obesity on vascular function are still poorly understood. The current study was designed to evaluate the effect of early obesity on coronary endothelial function in a new animal model of swine obesity. As to method, juvenile domestic crossbred pigs were randomized to either high-fat/high-calorie diet (HF) or normal chow diet for 12 wk. Coronary microvascular permeability and abdominal wall fat were determined by using electron beam computerized tomography. Epicardial endothelial function and oxidative stress were measured in vitro. Systemic oxidative stress, renin-angiotensin activity, leptin levels, and parameters of insulin sensitivity were evaluated. As a result, HF pigs were characterized by abdominal obesity, hypertension, and elevated plasma lysophosphatidylcholine and leptin in the presence of increased insulin sensitivity. Coronary endothelium-dependent vasorelaxation was reduced in HF pigs and myocardial microvascular permeability increased compared with those values in normal pigs. Systemic redox status in HF pigs was similar to that in normal pigs, whereas the coronary endothelium demonstrated higher content of superoxide anions, nitrotyrosine, and NADPH-oxidase subunits, indicating increased tissue oxidative stress. In conclusion, the current study shows that early obesity is characterized by increased vascular oxidative stress and endothelial dysfunction in association with increased levels of leptin and before the development of insulin resistance and systemic oxidative stress. Vascular dysfunction is therefore an early manifestation of obesity and might contribute to the increased cardiovascular risk, independently of insulin resistance.     

La dysfonction érectile, un marqueur précoce d’atteinte cardio-vasculaire

Erectile dysfunction (ED) affects approximately 100 million men in the world and 50% of men between the ages of 40 and 70 years. The commonest cause is a vascular disorder of penile arteries. ED may therefore be a an early marker of cardiovascular disease (CVD). The main arguments in favour of this assertion are primarily epidemiological, but also pathophysiological, as control of cardiovascular risk factors such as smoking, obesity and hypertension may prevent not only CVD, but also ED. This relationship is particularly strong in diabetic patients, in whom ED can be considered to be an element able to identify patients at risk of asymptomatic heart disease. From a pathophysiological point of view, small calibre penile vessels present signs of obstruction earlier than larger vessels because they are more sensitive to even minor haemodynamic changes. There is also a significant correlation between the severity of ED and the number of vessels affected in patients with coronary artery disease. Endothelial dysfunction is the common denominator underlying these diseases and therefore represents a major cause of ED. Preliminary studies have shown that PDE-5 inhibitors can reduce symptoms, improve exercise tolerance, and reduce endothelial dysfunction in patients after cardiac arrest and in diabetics. In the years to come, ED may therefore be added to the classical cardiovascular risk factors and could characterize a population with an increased risk of coronary artery disease.     

Cardiovascular proteomic analysis

Here, we report on our proteomic studies in the field of cardiovascular medicine. Our research has been focused on understanding the role of proteins in cardiovascular disease with a particular focus on epigenetic regulation and biomarker discovery, with the objective of better understanding cardiovascular pathophysiology to lead to the development of new and better diagnostic and therapeutic methods. We have used mass spectrometry for over 5 years as a viable method to investigate protein-protein interactions and post-translational modifications in cellular proteins as well as a method to investigate the role of extra-cellular proteins. Use of mass spectrometry not only as a research tool but also as a potential diagnostic tool is a topic of interest. In addition to these functional proteomics studies, structural proteomic studies are also done with expectations to allow for pinpoint drug design and therapeutic intervention. Collectively, our proteomics studies are focused on understanding the functional role and potential therapeutically exploitable property of proteins in cardiovascular disease from both intra-cellular and extra-cellular aspects with both functional as well as structural proteomics approaches to allow for comprehensive analysis.