LDL and atherogenesis

Taken from: http://ethesis.helsinki.fi/

2.2.1. LDL and atherogenesis

LDLs transport about 75% of the total cholesterol in blood circulation. Evidence exists that LDL cholesterol is a critical atherogenic factor (Grundy 1995,1997, Frishman 1998). A large number of epidemiologic studies have demonstrated a strong positive correlation between elevated LDL cholesterol levels and the development of coronary artery disease (CAD) (Kannell et al 1979, Krauss 1987, Genest and Cohn 1995, Frishman 1998). Genetic studies have also documented that inheritable hypercholesterolemias (familial hypercholesterolemia, familial defective apoB-100), mainly with elevated levels of LDL cholesterol, are the primary cause of premature CAD (Goldstein et al. 1973, Tybjaerg-Hansen et al. 1992). In addition, apoB and LDL particles have been identified in atherosclerotic plaques (Hoff et al. 1979a, Hoff et al. 1979b) and in vitro studies have shown that elevated LDL levels damage endothelial cell (EC) layer and penetrate into the arterial intima. The accumulation of LDL in the arterial wall initiates monocyte and smooth muscle cell migration and transforms macrophages and smooth muscle cells into cholesterol-loaded foam cells, which are the major cell components found in the plaque (Goldstein et al 1979, Brown and Goldstein 1983). Furthermore, pathological studies have demonstrated that the lowering of LDL-cholesterol is associated with reduced severity of atherosclerotic lesion and improvement of cardiac functional parameters (Zambon and Hokanson 1998). For example, reduction in cholesterol levels may reduce the susceptibility of LDL to oxidation which is a causal factor for the initiation and progression of atherosclerosis. Protection of LDL from oxidation could increase nitric oxide bioavailability and improve endothelium-dependent vasomotor, anti-inflammatory, and anticoagulant properties of the endothelium (Guetta and Cannon 1996). Finally, clinical studies have shown that lowering of LDL cholesterol has been associated with the reduction of CAD morbidity and mortality (Gotto 1995). The Scandinavian Simvastatin Survival Study (4S) showed that the lipid-lowering agent simvastatin significantly reduced the risk of coronary death and major coronary events in 4444 patients with coronary disease over the median follow-up period of 5.4 years (Scandinavian Simvastatin Survival Study Group 1994). These effects were presumed to be due to the beneficial reduction of serum lipids and lipoproteins, in which LDL cholesterol was reduced by 35%. The best evidence supporting lipid-lowering therapy for primary prevention comes from the West of Scotland Study (Shepherd et al. 1995). In this study, treatment with pravastatin resulted in significant reduction in nonfatal myocardial infarctions and death due to CAD. Taken together, these studies strongly support the importance of LDL in atherogenesis.