Review articleHDL and arteriosclerosis: beyond reverse cholesterol transport
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).
References (207)
- et al.
High density lipoprotein cholesterol as a predictor of coronary heart disease. The PROCAM experience and pathophysiological implication for reverse cholesterol transport
Atherosclerosis
(1996) - et al.
Associations of obesity markers, insulin, and sex hormones with HDL-cholesterol levels in Turkish and German individuals
Atherosclerosis
(1999) - et al.
Lipoproteins may provide fatty acids necessary for human lymphocyte proliferation by both low-density receptor-dependent and -independent mechanisms
J. Biol. Chem.
(1989) - et al.
Stimulation of proliferation in stationary primary cultures of monkey aortic smooth muscle cells: I. Effects of lipoprotein fractions of hyperlipemic serum and lymph
Exp. Mol. Pathol.
(1976) - et al.
Stimulation of proliferation in stationary primary cultures of monkey aortic smooth muscle cells: II. Effect of varying concentrations of hyperlipemic serum and low density lipoproteins of varying dietary fat origins
Atherosclerosis
(1976) - et al.
Growth-stimulating effect of lipoproteins on human arterial smooth-muscle cells and lung fibroblasts is due to apo B-containing lipoproteins, type LDL and VLDL, and requires LDL receptors
Biochim. Biophys. Acta
(1995) - et al.
Modulation of gene expression by high and low density lipoproteins in human vascular smooth muscle cells
Biochem. Biophys. Res. Commun.
(1991) - et al.
Lipoproteins induce expression of the early growth response gene-1 in vascular smooth muscle cells from rat
Biochem. Biophys. Res. Commun.
(1993) - et al.
High density lipoprotein increases intracellular calcium levels by releasing calcium from internal stores in human endothelial cells
Atherosclerosis
(1999) - et al.
Rapid purification and activity of apolipoprotein C1 on the proliferation of bovine vascular endothelial cells in vitro
Biochim. Biophys. Acta
(1984)
Proliferative effect of high density lipoprotein (HDL) and HDL fractions (HDL1,2, HDL3) on virus transformed lymphoblastoid cells
Biochim. Biophys. Acta
High density lipoprotein 3 binding sites are related to DNA biosynthesis in the adenocarcinoma cell line A549
J. Lipid Res.
High density lipoprotein reduces epidermal growth factor-induced DNA synthesis in vascular smooth muscle cells
Atherosclerosis
Primary endothelial dysfunction: atherosclerosis
J. Mol. Cell. Cardiol.
The atherogenic lipoprotein phenotype and vascular endothelial dysfunction
Atherosclerosis
Constantly low HDL-cholesterol concentration relates to endothelial dysfunction and increased in vivo LDL-oxidation in healthy young men
Atherosclerosis
Endothelium-dependent and -independent functions are impaired in patients with coronary heart disease
Atherosclerosis
Protective effect of high density lipoprotein on endothelium-dependent vasodilation
Int. J. Cardiol.
Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia
J. Am. Coll. Cardiol.
Effects of high-density lipoprotein on acetylcholine-induced coronary vasoreactivity
Am. J. Cardiol.
High density lipoprotein prevents oxidized low density lipoprotein-induced inhibition of endothelial nitric-oxide synthase localization and activation in caveolae
J. Biol. Chem.
Effects of high-density lipoproteins on intracellular pH and proliferation of human vascular endothelial cells
Atherosclerosis
High-density lipoproteins protect endothelial cells from tumor necrosis factor-alpha-induced apoptosis
Biochem. Biophys. Res. Commun.
Lipolyzed hypertriglyceridemic serum and triglyceride-rich lipoprotein cause lipid accumulation in and are cytotoxic to cultured human endothelial cells. High density lipoproteins inhibit this cytotoxicity
Thromb. Res.
High-density lipoprotein and its apolipoproteins inhibit cytolytic activity of complement. Studies on the nature of inhibitory moiety
Biochim. Biophys. Acta
Interaction between apolipoproteins A-I and A-II and the membrane attack complex of complement. Affinity of the apoproteins for polymeric C9
J. Biol. Chem.
Pharmacodynamic profile of prostacyclin
Am. J. Cardiol.
Is the anti-atherosclerotic potency of HDL modulated by the origin of HDL?
Prostaglandins Leukot. Essent. Fatty Acids
Differential influence of lipoproteins isolated from women and men on the activity of the PGI2 synthetase activity
Prostaglandins Med.
Influence of human low density and high density lipoprotein cholesterol on the in vitro prostaglandin I2 synthase activity
Biochim. Biophys. Acta
Stimulation of arterial endothelial cell prostacyclin synthesis by high density lipoproteins
J. Biol. Chem.
Effect of human native low-density and high-density lipoproteins on prostaglandin production by mouse macrophage cell line P388D1: possible implications in the pathogenesis of atherosclerosis
Biochim. Biophys. Acta
The effect of high density lipoprotein subfractions on endothelial eicosanoid secretion
Thromb. Res.
Regulation of PGI2 activity by serum proteins: serum albumin but not high density lipoprotein is the PGI2 binding and stabilising protein in human blood
Biochem. Biophys. Acta
Human high density lipoproteins stimulate endothelin-1 release by cultured human renal proximal tubular cells
Kidney Int.
Stimulation of endothelin-1 release by low density and very low density lipoproteins in cultured human endothelial cells
Atherosclerosis
Physiological role and clinical relevance of high-density lipoprotein subclasses
Curr. Opin. Lipidol.
A solely apolipoprotein E containing plasma lipoprotein with electrophoretic gamma-mobility takes up cellular cholesterol
Proc. Natl. Acad. Sci. USA
Lipoproteins containing apolipoprotein A-IV but not apolipoprotein A-I take up and esterify cell-derived cholesterol in plasma
Arterioscler. Thromb. Vasc. Biol.
High density lipoproteins—the clinical implication of recent studies
N. Engl. J. Med.
Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster Study
Am. J. Cardiol.
Familial lipoprotein disorders in patients with coronary disease
Circulation
Prevention of coronary heart disease by raising of high density lipoprotein cholesterol
Curr. Opin. Lipidol.
Systemic inflammatory parameters in patients with atherosclerosis of the coronary and peripheral arteries
Arterioscler. Thromb. Vasc. Biol.
High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease
Circulation
Short-term prognostic value of lipid measurements for coronary events in patients with angina pectoris
Thromb. Haemost.
An overview of reverse cholesterol transport
Europ. Heart J.
Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species
J. Lipid Res.
Acceleration of reverse cholesterol transport
Curr. Opin. Cardiol.
HDL and atherosclerosis: role of cholesterol efflux and reverse cholesterol transport
Arterioscler. Thromb. Vasc. Biol.
Cited by (496)
High-density Lipoprotein Cholesterol and the Risk of Future Retinal Artery Occlusion Development: A Nationwide Cohort Study
2022, American Journal of OphthalmologyGenetics and regulation of HDL metabolism
2022, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsNutritional Fuelling for Microgravity Environment of Space Missions
2024, Current Nutrition and Food ScienceDETERMINATION OF THE RELATIONSHIP BETWEEN DNA METHYLATION STATUS OF KLOTHO AND ARNTL GENES WITH HYPERTENSION
2023, Balkan Journal of Medical GeneticsRole of paraoxonase 1 activity and PON1 gene polymorphisms in sickle cell disease
2023, Scientific ReportsEstimation of Fibulin-1, Chemerin and Omentin-1 in Iraqi Women with Polycystic Ovary Syndrome-Associated Infertility
2023, Al-Rafidain Journal of Medical Sciences