Elsevier

Atherosclerosis

Volume 161, Issue 1, March 2002, Pages 1-16
Atherosclerosis

Review article
HDL and arteriosclerosis: beyond reverse cholesterol transport

https://doi.org/10.1016/S0021-9150(01)00651-7Get rights and content

Abstract

The inverse correlation between serum levels of high density lipoprotein (HDL) cholesterol and the risk of coronary heart disease, the protection of susceptible animals from atherosclerosis by transgenic manipulation of HDL metabolism, and several potentially anti-atherogenic in vitro-properties have made HDL metabolism an interesting target for pharmacological intervention in atheroslcerosis. We have previously reviewed the concept of reverse cholesterol transport, which describes both the metabolism and the classic anti-atherogenic function of HDL (Arterioscler. Thromb. Vasc. Biol. 20 2001 13). We here summarize the current understanding of additional biological, potentially anti-atherogenic properties of HDL. HDL inhibits the chemotaxis of monocytes, the adhesion of leukocytes to the endothelium, endothelial dysfunction and apoptosis, LDL oxidation, complement activation, platelet activation and factor X activation but also stimulates the proliferation of endothelial cells and smooth muscle cells, the synthesis of prostacyclin and natriuretic peptide C in endothelial cells, and the activation of proteins C and S. These anti-inflammatory, anti-oxidative, anti-aggregatory, anti-coagulant, and pro-fibrinolytic activities are exerted by different components of HDL, namley apolipoproteins, enzymes, and even specific phospholipids. This complexity further emphasizes that changes in the functionality of HDL rather than changes of plasma HDL-cholesterol levels determine the anti-atherogenicity of therapeutic alterations of HDL metabolism.

Section snippets

Short overview of HDL structure, heterogeneity, and anti-atherogenic potential

High-density lipoproteins (HDL) are a fraction of serum lipoproteins characterized by similar molecule density (1.063<d<1.21 g/ml) and size (5–17 nm in diameter). As a result of qualitative and quantitative differences in lipid, protein and enzyme content HDL particles are multi-shaped molecules with varying density, fluidity, charge, and anti-genicity. The most frequently used method of lipoprotein isolation—isopycnic ultracentrifugation—separates two major HDL fractions—HDL2 (d=1.063−1.0125

HDL induces cell proliferation

Several studies revealed modulatory effects of HDL on cell proliferation. However, the current information concerning growth-modulatory effects of HDL is controversial. In some studies HDL was found to stimulate cell growth in combination with serum, lipoprotein-deficient serum, and/or defined growth factors such as platelet-derived growth factor (PDGF), epithelial growth factor (EGF), fibroblast growth factor (FGF), insulin, or transferrin [17], [18], [19], [20]. In other studies HDL did not

HDL protects endothelial cells

The endothelium secretes a number of humoral factors which regulate vasoconstriction and vasodilatation of blood vessels, modulate platelet activation, coagulation and fibrinolysis, and affect the proliferation and differentiation of smooth muscle cells [45]. One of the most important products of endothelial cells synthesized in response to a multitude of physiological stimuli is nitric oxide (NO). Through the action of nitric oxide the endothelium induces relaxation of blood vessels,

HDL affects secretory functions of endothelium

HDL affects several secretory functions of endothelial cells. Prostacyclin (PGI2) produced in endothelial cells by cyclooxygenase has a potent vasorelaxing activity, inhibits platelet activation, and diminishes the release of growth factors such as FGF and EGF, which stimulate the local proliferation of smooth muscle cells [77]. Physiological concentrations of HDL stimulate PGI2 production [78], [79], [80]. The stimulatory effect of HDL on PGI2 depends on two factors. First, HDL supplies

HDL inhibits endothelial adhesion and activation of leukocytes

Adhesion of leukocytes to endothelial cells and interaction of leukocytes with smooth muscle cells play a crucial role in the development of the atherosclerotic plaque. Interaction of monocytes with endothelial cells is mediated by adhesion molecules located on the surface of these cells which include the vascular cell adhesion molecule-1 (VCAM-1), the intercellular adhesion molecule-1 (ICAM-1) and E-selectin. VCAM-1 and ICAM-1 mediate adhesion of mononuclear cells including monocytes and

HDL regulates coagulation and fibrinolysis

Some epidemiological studies demonstrated an association between coagulation and fibrinolysis, and the incidence of the coronary heart disease. For example, the Northwick Park Heart Study has shown that the pro-coagulative activity of factor VII is a potent predictor of death from CHD [114], [115], [116]. In addition, high levels of the plasminogen activator inhibitor type I (PAI-I) which reflect reduced fibrinolytic plasma activity, are associated with increased cardiovascular risk [117], [118]

HDL inhibits platelet activation

HDL also affects the activation of thrombocytes. Recently, Naqui et al. demonstrated that low HDL-C is an independent predictor of acute platelet-dependent thrombus formation [135]. In vitro HDL inhibits thrombin-, collagen-, ADP-, and adrenalin- induced platelet aggregation [136], [137], [138]. This effect was observed in platelet-rich plasma and in isolated platelets. HDL also inhibits thrombin-induced binding of fibrinogen on platelets [139]. In this case HDL behaves like an endogenous

HDL acts as an anti-oxidant

The oxidation of LDL is commonly considered to be a major event in the initiation and development of atherosclerosis [159]. OX-LDL is a chemoattractant for monocytes, transforms macrophages into foam cells, exerts cytotoxic effects on endothelial cells, increases thrombocyte activation, stimulates migration and proliferation of smooth muscle cells, and antagonizes the vasodilative effect of nitrogen oxide [160], [161]. Several authors have shown that HDL significantly reduces the oxidative

Concluding remarks

In addition to reverse cholesterol transport a number of potentially anti-atherogenic activities are exerted by HDL. It is important to emphasize that most of these functions are exerted not by most apoproteins, but rather by lipids or enzymes associated with HDL. The major drawback of the studies of the pleiotropic functions of HDL is, that they were performed in vitro or were based on purely statistical reasoning. There is a strong need for in vivo studies to validate the relevance of various

Acknowledgements

Dr Arnold von Eckardstein is supported by grants from the European Union on ‘The Anti-atherogenicity of HDL’ (grant no. BIOMED2 BMH4-CT98-3699) and ‘Macrophage and Plaque Stability’ (grant no. QLG1-1999-01007).

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