The Modern Art of Atherosclerosis

Abstract

Atherosclerosis is a disease of large arteries that accounts for more than 50% of all deaths in the developed countries1 and, according to the World Health Organization prediction, it will gain a status of the major morbidity cause worldwide by the year 2010.2 Atherosclerosis is widely viewed as an inflammatory disease with hypercholesterolemia being a dominant underlying risk factor.3,4 It is believed to be initiated by retention of LDL particles in the lesion-prone areas, which is followed by monocyte recruitment and their differentiation into cholesterol-laden macrophage foam cells.1,5 Excessive cholesterol accumulation in macrophages exaggerates innate immune response that is manifested by upregulated production and secretion of inflammatory cytokines and chemokines, thus dramatically amplifying initial signal originated from the injured artery.6 See page 519 Despite the overall consensus on the causative roles of excessive cholesterol build-up and inflammation in the development and progression of atherosclerosis, the relationship between aberrant cholesterol metabolism and exaggerated innate immune response has not been totally established. Recent reports showing reduced inflammation in association with the cholesterol-lowering statin therapy provided indirect evidence linking cholesterol metabolism with regulation of immune response.7 However, this class of cholesterol lowering drugs not only inhibits cholesterol biosynthesis but also suppresses the synthesis of isoprenoids such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Thus, inhibition of prenylation pathways such as those required for activation of Ras and Rho GTPase family proteins may be responsible for some of the …