Cellular processes in atherogenesis: potential targets of Ca2+ channel blockers.
Atherosclerosis is characterized by increased endothelial permeability, monocyte infiltration, intimal smooth muscle cell (SMC) proliferation, platelet aggregation and the accumulation of lipids, calcium and extracellular matrix components in the vessel wall. In various animal studies and recently in humans it could be established that Ca2+ channel blockers delayed the progression of the atherosclerotic process at the stage of early lesions. This review surveys the interaction of Ca2+ channel blockers with various membrane proteins (purinergic receptors, nucleoside transporter, peripheral benzodiazepine receptors, multi-drug resistance protein) which are involved in signal transduction and their potential impact on the observed antiatherosclerotic effects. Although the precise mechanisms have yet to be fully elucidated, it has been clearly shown that these drugs inhibit smooth muscle cell proliferation and migration, improve cellular lipoprotein metabolism in vascular cells, alter phospholipid turnover, decrease platelet adhesion in the vessel wall, reduce extracellular matrix synthesis and protect against radical induced cell damage. Most of these effects are independent of Ca2+ flux across voltage-operated Ca2+ channels. However, all these processes are relevant to the pathogenesis of atherosclerosis and therefore the elucidation of the antiatherogenic mechanisms of Ca2+ channel blockers at the cellular level is of great interest. The future development of Ca2+ channel blockers with altered molecular structures optimized for their antiatherosclerotic targets may provide a useful tool in the therapy of atherosclerosis and risk factor intervention. The protective mechanisms are related to a stabilization of cell membrane integrity, the modulation of secretory activities and cell/cell communication processes rather than to a lowering of plasma lipoprotein levels.
Schmitz
G
G
Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster, Germany.
Hankowitz
J
J
Kovacs
E M
EM
D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism / Q000503:physiopathology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D005109:Extracellular Matrix / Q000187:drug effects / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D010586:Phagocytes / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology; D011983:Receptors, Purinergic / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011963:Receptors, GABA-A; D011983:Receptors, Purinergic