Cholesterol, calcium and atherosclerosis: is there a role for calcium channel blockers in atheroprotection?

摘要: It is well known that the atherogenic dyslipidemias of either elevated serum LDL or reduced HDL levels correlate with degree and severity atherosclerosis. However, how this leads to atherogenesis poorly understood. A role for cellular oxidative stress mediated by oxidized has gained widespread acceptance, but pathway unlikely be sole signal. Recent evidence obtained from arterial smooth muscle cells (SMC) endothelial (EC) consistent another may explain, in part, early alterations contributing initiation modifications. This involves enrichment cell plasma membrane cholesterol. In SMC, vitro (cell culture) vivo (cholesterol feeding) experiments demonstrate cholesterol SMC occurs rapidly associated an increase bilayer width, calcium permeability, proliferation. Removal excess human restores these alterations, suggesting structural 'defect' mediates changes function. vitro, increased permeability inhibitable channel blockers (CCBs), vivo, a 'leak' develops virtually uninhibitable. not surprising literature on application CCBs atheroprotection wholly convincing. advent new third generation CCBs, hope arises. One first amlodipine (Norvasc), charged dihydropyridine remarkable pharmacologic profile. First, it markedly lipophilic allowing partition readily into membranes. Second, ability re-order, restore, 'swollen' back normal atherosclerotic SMC. Third, potent antioxidant properties. Fourth, appears inhibit expression variety genes implicated atherogenesis. Fifth, CCB. Amlodipine demonstrated both rabbit subhuman primate models disease. We propose induced cholesterol, which modulate phenotype, are through combination its varied The potential currently being investigated trial (PREVENT trial) results will determine relevance preclinical findings humans.