The atherogenic lipoprotein phenotype and vascular endothelial dysfunction
Introduction
Plasma low density lipoprotein-cholesterol (LDL-cholesterol) has long been regarded as the key lipid fraction in the pathogenesis of atherosclerosis. This view has recently been reinforced by the results of studies showing that lowering plasma LDL cholesterol concentrations using statins is an effective primary and secondary prevention measure for coronary artery disease (CAD) 1, 2. However, there is accumulating evidence that elevated plasma triglycerides and related abnormalities constitute an independent cardiovascular risk factor at least as important as cholesterol 3, 4, 5, 6, 7. Raised plasma triglyceride-rich lipoproteins are associated with low high-density lipoprotein cholesterol (HDL-cholesterol) and small, dense LDL particles and together comprise the atherogenic lipoprotein phenotype (ALP) [8]. The clinical importance of this ALP pattern probably exceeds that of LDL-cholesterol, because many more CAD patients are found to have this trait than hypercholesterolaemia [9]. The pathogenetic basis for the apparent relationship between elevated triglyceride-rich lipoproteins and CAD is still uncertain. We propose that endothelial damage, in part mediated by increased oxidative stress, is one mechanism whereby elevated triglyceride-rich particles (and related metabolic features) may be causally associated with atherogenesis.
Section snippets
The atherogenic lipoprotein profile, insulin resistance and free fatty acids
Elevations in free fatty acids (FFAs) are observed in abdominal obesity, non-insulin dependent diabetes mellitus (NIDDM) and other insulin resistant states [10]. FFAs are the major substrates for hepatic triglyceride synthesis [11]and impaired suppression of circulating plasma levels of FFAs by insulin plays a major role in the initiation of the atherogenic lipoprotein cascade. The consequent increased hepatic secretion of triglyceride-rich very low density lipoprotein (VLDL) into the plasma
Endothelium and endothelial dysfunction
The vascular endothelium is an active organ, synthesising and responding to vasodilator and vasoconstrictor agents, regulating the balance between thrombosis and fibrinolysis, and interacting with monocytes and inhibiting platelet activity [14]. Production of the inorganic gas nitric oxide (NO) is believed to be integral to many of these functions. NO, formed from l-arginine by a constitutive form of the enzyme nitric oxide synthase, inhibits platelet aggregation and adhesion, modulates smooth
Oxidative stress
Available evidence suggests that the extent of endothelial vasodilator dysfunction might reflect the degree of oxidative stress imposed on the endothelium by cardiovascular risk factors. This assumption is based upon reports that antioxidants such as vitamin E and vitamin C, and probucol ameliorate the degree of endothelial vasomotor dysfunction 23, 25, and in the case of vitamin E improve coronary outcome 26, 27. Excessive production of reactive species in the form of superoxide anions in
Summary
We have reviewed the possible mechanisms by which elevations in triglyceride-rich lipoproteins (and related metabolic perturbances) may mediate endothelial dysfunction. There is evidence to suggest that triglyceride-rich particles may be directly damaging to the endothelium; this may be principally via oxidative mechanisms. Triglyceride-rich particles can cross the endothelial barrier and enter the arterial wall, thus placing them in a position to promote direct endothelial damage. These
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