ATHEROGENIC LIPOPROTEIN AND ENDOTHELIAL DYSFUNCTION

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ATHEROGENIC LIPOPROTEIN AND ENDOTHELIAL DYSFUNCTIONC

CHAPTER TWO

Literature review

Atherogenic lipids, particularly oxidized low-density lipoprotein, are responsible for a wide range of cellular dysfunctions within the vessel wall. The effects on endothelial cells disrupt normal control of vasomotion, with a reduction of effective nitric oxide activity, the development of a procoagulant surface, chronic low-grade inflammation, and abnormal cell growth. These changes are central not only in the development of atherosclerosis but also in the evolution of both stable and unstable ischemic syndromes. There is growing evidence that these abnormal changes in cell function respond rapidly to changes in the atherogenic lipids. Certain cell functions can improve within hours or days of cholesterol lowering.

The vascular endothelium plays a key role in the local regulation of vascular tone by the release of vasodilator substances (i.e. endothelium-derived relaxing factor (EDRF = nitric oxide, NO) and prostacyclin) and vasoconstrictor substances (i.e. thromboxane A2, free radicals, or endothelin). Using either agents like acetylcholine or changes in flow to stimulate the release of EDRF (NO), clinical studies have revealed the importance of EDRF in both basal and stimulated control of vascular tone in large epicardial coronary arteries and in the coronary microcirculation. The regulatory function of the endothelium is altered by cardiovascular risk factors or disorders such as hypercholesterolemia, chronic smoking, hypertension or chronic heart failure. Endothelial dysfunction appears to have detrimental functional consequences as well as adverse longterm effects, including vascular remodelling. Endothelial dysfunction is associated with impaired tissue perfusion particularly during stress and paradoxical vasoconstriction of large conduit vessels including the coronary arteries. These effects may cause or contribute to myocardial ischemia. Several mechanisms may be involved in the development of endothelial dysfunction, such as reduced synthesis and release of EDRF or enhanced inactivation of EDRF after its release from endothelial cells by radicals or oxidized low-density lipoprotein (LDL). Increased plasma levels of oxidized LDL have been noted in chronic smokers and are related to the extent endothelial dysfunction, raising the possibility that chronic smoking potentiates endothelial dysfunction by increasing circulating and tissue levels of oxidized LDL. In heart failure, cytokines and/or reduced flow (reflecting reduced shear stress) may be involved in the development of endothelial dysfunction and can be reversed by physical training. Other mechanisms include an activated renin-angiotensin system (i.e. postmyocardial infarction) with increased breakdown of bradykinin by enhanced angiotensin converting enzyme (ACE) activity. There is evidence that endogenous bradykinin is involved in coronary vasomotor control both in coronary conduit and resistance vessels. ACE inhibitors enhance endothelial function by a bradykinin-dependent mechanism and probably also by blunting the generation of superoxide anion. Endothelial dysfunction appears to be reversible by administering L-arginine, the precursor of nitric oxide, lowering cholesterol levels, physical training, antioxidants such as vitamin C, or ACE inhibition.

An inflammatory disease involving the presence of both intra- and extracellular lipid deposits in arteries. More than 20 yr ago, Zilversmith (1) hypothesized that processes that occur during the postprandial phase are proatherogenic. Several clinical and experimental data suggest, in fact, that elevated postprandial lipemia is related to the presence of coronary artery disease (CAD) (2) and is an independent risk factor for coronary atherosclerosis (3). The role of the endothelium in the pathogenesis of cardiovascular diseases is well recognized. A close correlation exists between the presence of cardiovascular risk factors and a decrease of the endothelial vasodilator function. (Endothelial function is reduced in patients with CAD (6, 7) or myocardial ischemia (8, 9). Furthermore, endothelial dysfunction predicts the recurrence of cardiovascular events (4, 10, 11) and progression of atherosclerotic disease.

The control of the main risk factors improves endothelial function. In fact, total cholesterol fasting levels (12, 13) are inversely related to the endothelial function; this condition is rapidly improved upon cholesterol reduction as best illustrated by the dramatic changes occurring after low-density lipoprotein (LDL) apheresis in familial hypercholesterolemia patients

The endothelial function is transiently reduced in normo-

Abbreviations: Apo, Apolipoprotein; AUC, area under the curve; CAD, coronary artery disease; C-RLP, cholesterol remnant lipoprotein; FMD, flow-mediated dilation; LDL, low-density lipoprotein; OFL, oral fat load; RLP, remnant lipoprotein plasma; TG, triglyceride(s).

JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

1.42%, P < 0.01). Cholesterol in RLPs increased steadily up to 6 h and decreased at 8 h (T0 0.53 0.10, T6 0.81 0.11, T8 0.73 0.13 mmol/liter). Fasting levels of triglycerides and cholesterol-RLPs (C-RLPs) correlated significantly with FMD at baseline. The decrease in endothelial function at 6 h also significantly correlated with the area under the curve of triglycerides (R 0.53, P 0.04). Postprandial C-RLPs (area under the curve), however, showed the best correlation with the decrease of FMD (R 0.63, P 0.012). The correlation persisted in a multivariate analysis.

We concluded that C-RLPs contribute significantly to the endothelial dysfunction occurring during the postprandial lipemia. (J Clin Endocrinol Metab 89: 2946–2950, 2004)

cholesterolemic and hypercholesterolemic subjects during postprandial lipemia (15–18). The lipoprotein fraction(s) that may be involved in determining such an effect are unknown. Fasting remnant lipoprotein (RLP) plasma levels correlate directly with the endothelial dysfunction in peripheral (19) and coronary arteries (20), and changes in the postprandial phase correlate with the fasting endothelial function (21). Furthermore, RLP levels are strongly associated with angiographically verified progression of focal coronary atherosclerosis (22), and their lowering with gemfibrozil prevents vein graft stenosis (22). In addition, RLP levels are significantly increased after a fat loading (23).

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