Research review
Effects of Adipocyte-Derived Cytokines on Endothelial Functions: Implication of Vascular Disease

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Adipose tissue has recently emerged as an active endocrine organ that secretes a variety of metabolically important substances, collectively called adipocytokines or adipokines. In this review we summarize the effects of the adipokines leptin, adiponectin, and resistin on the vasculature and their potential role for pathogenesis of vascular disease. Leptin is associated with arterial wall thickness, decreased vessel distensibility, and elevated C reactive protein (CRP) levels. Leptin possesses procoagulant and antifibrinolytic properties, and it promotes thrombus and atheroma formation, probably through the leptin receptors by promoting vascular inflammation, proliferation, and calcification, and by increasing oxidative stress. Research for development of pharmacologic antagonism for the leptin receptor is currently under way. Adiponectin inhibits the expression of the adhesion molecules ICAM-1, VCAM-1, and P selectin. Therefore, it interferes with monocyte adherence to endothelial cells and their subsequent migration to the subendothelial space, one of the initial events in the development of atherosclerosis. Adiponectin also inhibits the transformation of macrophages to foam cells in vitro and decreases their phagocytic activity. Resistin, discovered in 2001, represents the newest of the adipokines and was named for its ability to promote insulin resistance. Resistin increases the expression of the adhesion molecules VCAM-1 and ICAM-1, up-regulates the monocyte chemoattractant chemokine-1, and promotes endothelial cell activation via ET-1 release. Although many aspects of its function need further clarification, it appears that resistin will add significantly to our knowledge of the pathophysiology of vascular disease and the metabolic syndrome.

Introduction

Atherosclerosis is a disease process that starts in fetal life [1] and is associated with a significant morbidity and mortality. Leading predisposing factors include hyperlipidemia, cigarette smoking, hypertension, obesity, and diabetes. Type 2 diabetes is closely associated with obesity and is caused by a relative resistance to insulin, which has recently emerged as a significant vascular hormone with important links to the pathophysiology of atherosclerotic vascular disease [2].

Recent studies have transformed our thinking about the adipocyte. It is no longer viewed as a passive energy storage tissue; instead, it has been recognized to produce a number of metabolically and hormonally active substances, collectively called adipokines or adipocytokines [3]. These adipokines consist of polypeptides but also nonprotein factors that are known to affect different functional categories including immunity function (complement factors and haptoglobin), endocrine function (leptin, sex steroids, and various growth factors), metabolic function (fatty acids, adiponectin, and resistin), and cardiovascular function (angiotensinogen and plasminogen activator inhibitor-1). Adiponectin, leptin, and resistin may have synergistic or competitive activity to insulin. Insulin resistance is an important factor for the development of coronary heart disease, supported by studies in animal models [4] and humans [5]. Therefore, these investigations have the potential to provide useful insight into the pathogenesis of vascular disease.

In this review, we present the current understanding of the complex role of the adipocyte-derived hormones leptin, adiponectin, and resistin on the endothelial cell function and the pathogenesis of atherosclerotic vascular disease. Mechanisms of action and data from animal and human studies, as well as controversies surrounding their function, are discussed.

Section snippets

Leptin

Leptin (from the Greek word leptos meaning thin) was identified by positional cloning in 1993 [6] as a key molecule in the regulation of body weight and energy balance. Subsequent research has revealed that the effect of leptin is not restricted to appetite and food intake. Leptin is a pleiotropic molecule with a broad variety of different biological actions, including reproductive function, regulation of the hypothalamic-pituitary-adrenal (HPA) axis, glucose and insulin metabolism, lipolysis,

Adiponectin

Human adiponectin was isolated from the plasma as gelatin binding protein of 28 kDa [49]. It contains 244 amino acid residues and consists of a 20-residue signal sequence, an N-terminal region without homology to any known proteins, a collage-like region, and a C-terminal globular domain. Under normal conditions, adiponectin gene is expressed almost exclusively in the adipose tissue. However, adiponectin mRNA appears in hepatocytes after treatment with carbon tetrachloride or IL-6 [50, 51].

Resistin

Resistin is a member of a newly discovered family of cysteine-rich secretory proteins called “resistin-like molecules” (RELM) or “found in the inflammatory zone” (FIZZ). It was initially discovered in a screen to identify potential targets of the thiazolidinedione (TZD) class of insulin sensitizers in 3T3-L1 adipocytes [61]. Resistin is encoded by the Retn gene, and is secreted as a disulfide-linked dimer [62]. In mice, the retn gene is expressed almost exclusively in white adipose tissue and

Summary

The identification of adipokines is intriguing from both a theoretical and clinical point of view. There are several lines of evidence to support the notion that at least the three adipokines discussed above are involved in the pathogenesis of atherosclerotic disease (Fig. 1). As further data from human studies are accumulated, the role of adipokines will continue to evolve. The development of pharmacologic antagonists is a very attractive idea and may have implications for both the treatment

Acknowledgments

This work was supported by National Institutes of Health grants R01 HL61943, R01 HL65916, R01 HL60135, and R01 HL72716 (C. Chen); R21 AI49116 (Q. Yao); R01 HL75824 (Lumsden); and K08 HL076345 (Lin).

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