Schmitz G, Hankowitz J, Kovacs E M
Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster, Germany.
Atherosclerosis. 1991 Jun;88(2-3):109-32. doi: 10.1016/0021-9150(91)90074-d.
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.
动脉粥样硬化的特征是内皮通透性增加、单核细胞浸润、内膜平滑肌细胞（SMC）增殖、血小板聚集以及血管壁中脂质、钙和细胞外基质成分的积累。在各种动物研究以及最近在人体研究中已证实，钙通道阻滞剂在早期病变阶段可延缓动脉粥样硬化进程。这篇综述探讨了钙通道阻滞剂与参与信号转导的各种膜蛋白（嘌呤能受体、核苷转运体、外周苯二氮䓬受体、多药耐药蛋白）的相互作用及其对所观察到的抗动脉粥样硬化作用的潜在影响。尽管确切机制尚未完全阐明，但已明确表明这些药物可抑制平滑肌细胞增殖和迁移，改善血管细胞中的细胞脂蛋白代谢，改变磷脂周转，减少血小板在血管壁的黏附，减少细胞外基质合成并防止自由基诱导的细胞损伤。这些作用大多与跨电压门控钙通道的钙通量无关。然而，所有这些过程都与动脉粥样硬化的发病机制相关，因此在细胞水平阐明钙通道阻滞剂的抗动脉粥样硬化机制具有重要意义。未来开发针对抗动脉粥样硬化靶点优化分子结构的钙通道阻滞剂可能为动脉粥样硬化治疗和危险因素干预提供有用工具。其保护机制与细胞膜完整性的稳定、分泌活动的调节以及细胞/细胞通讯过程有关，而非与降低血浆脂蛋白水平有关。
