The smooth muscle cell membrane during atherogenesis: A potential target for amlodipine in atheroprotection

Background Atherosclerotic disease has been present in the human population apparently from the beginning of time. However, it has only been in the 20 th century that improvements in the control of infectious diseases have all owed the average life span to increase to the point where atherosclerosis h as been able to affect the general population. By the middle of the 20th ce ntury, atherosclerosis had reached epidemic levels, and it is currently pan demic and increasing worldwide. Despite its growing significance to health care, we still know relatively little about the cellular basis for plaque g enesis in the vessel wall. Current thinking holds that atherosclerosis is c aused by an unchecked chronic inflammatory process involving the cells of t he arterial wall and their interaction with LDL and various inflammatory ce lls. Considerable evidence suggests that the principal insults underlying a therogenesis are serum dyslipidemias and oxidative stress mediated primaril y by oxidized LDI. However, just how these insults alter the cell biology o f vascular cells and lead to the atherosclerotic phenotype is still under i ntense investigation. Moreover, recent clinical trials have provided eviden ce that certain classes of drugs, including newer calcium channel blockers (CCBs), can remodel the arterial smooth muscle cell (SMC) membrane and inhi bit the progression of atherosclerotic disease. Methods This review summarizes our current thinking on atherogenesis in the arterial SMC and considers recent developments regarding alterations in th e SMC membrane during the very early period of atherogenesis. We also discu ss how certain CCBs might operate to produce atheroprotection. Results The SMC membrane becomes enriched in unesterified cholesterol soon after the development of serum hypercholesterolemia. With excess membrane c holesterol, the membrane becomes thicker and develops distinct cholesterol domains. These alterations in the membrane increase the permeability of SMC to calcium and induce a variety of alterations in SMC function that contri bute to cellular atherogenic processes during plaque genesis. Amlodipine, a third-generation CCB, markedly inhibits the progression of lesions. The ex planation of this novel action may lie in the effects of this drug on vario us potential cellular targets. Conclusions Evidence is accumulating that excess membrane cholesterol may c ontribute to the cellular defects responsible for the transformation of the SMC to the atherosclerotic phenotype. Amlodipine, which has membrane-remod eling properties, is emerging as an important atheroprotective drug.