Luoma Pauli V
Institute of Biomedicine, Pharmacology, FIN-00014 University of Helsinki, Finland.
Cardiovasc Hematol Agents Med Chem. 2009 Oct;7(4):295-304. doi: 10.2174/187152509789541918.
Atherosclerotic cardiovascular disease is a major health problem worldwide. This article reviews studies clarifying the effects of gene-activating agents on the atherosclerotic vascular process, the occurrence of fatal and nonfatal atherosclerotic disease, and all-cause mortality. Studies originating in the 1970s linked drug-caused gene induction and high protein and cytochrome P450 concentrations in the liver with high apolipoprotein AI (apo AI) and HDL cholesterol (HDL-C) and reduced LDL cholesterol (LDL-C) levels in plasma and presented the view that the inducers, gene-activators, have beneficial exploitable effects against atherosclerosis. The following studies have shown that P450-enzymes respond to cholesterol accumulation and act in maintaining cholesterol homeostasis and that gene-activators act against the atherosclerotic process. The compounds include drugs indicated for dyslipidemias, such as statins, fibrates, niacin and cholestyramine, as well as compounds used for other purposes, including calcium channel blockers, angiotensin receptor blockers and glitazones. The compounds generate signaling mediators such as oxysterols and eicosanoids. The gene-activators upregulate, via the activation of nuclear receptors, genes encoding proteins such as apo AI and ATP-binding cassette (ABC) A1 transporters that efflux cellular cholesterol, transport it to the liver and excrete it into bile, and prevent cholesterol absorption in the intestine. Several statins, niacin, cholestyramine, calcium channel blockers, angiotensin receptor blockers, pioglitazone and etidronate regress atherosclerosis in coronary and /or carotid arteries. Other compounds, including fibrates, phenobarbital and alcohol also have positive antiatherogenic effects. Several gene-activators reduce mortality and / or morbidity from coronary heart disease and cerebrovascular disease, and also death from any cause.
动脉粥样硬化性心血管疾病是全球主要的健康问题。本文综述了一些研究，这些研究阐明了基因激活剂对动脉粥样硬化血管进程、致命和非致命性动脉粥样硬化疾病的发生以及全因死亡率的影响。始于20世纪70年代的研究将药物引起的基因诱导、肝脏中高蛋白和细胞色素P450浓度与血浆中高载脂蛋白AI（apo AI）、高密度脂蛋白胆固醇（HDL-C）以及降低的低密度脂蛋白胆固醇（LDL-C）水平联系起来，并提出诱导剂（即基因激活剂）对动脉粥样硬化具有有益的可利用作用这一观点。随后的研究表明，P450酶对胆固醇积累有反应，并在维持胆固醇稳态中起作用，且基因激活剂对动脉粥样硬化进程有对抗作用。这些化合物包括用于治疗血脂异常的药物，如他汀类药物、贝特类药物、烟酸和考来烯胺，以及用于其他目的的化合物，包括钙通道阻滞剂、血管紧张素受体阻滞剂和噻唑烷二酮类药物。这些化合物可产生信号介质，如氧化甾醇和类二十烷酸。基因激活剂通过激活核受体上调编码诸如apo AI和ATP结合盒（ABC）A1转运蛋白等蛋白质的基因，这些转运蛋白可将细胞内胆固醇外排，转运至肝脏并排泄到胆汁中，还能防止肠道吸收胆固醇。几种他汀类药物、烟酸、考来烯胺、钙通道阻滞剂、血管紧张素受体阻滞剂、吡格列酮和依替膦酸可使冠状动脉和/或颈动脉的动脉粥样硬化消退。其他化合物，包括贝特类药物、苯巴比妥和酒精也具有积极的抗动脉粥样硬化作用。几种基因激活剂可降低冠心病和脑血管疾病的死亡率和/或发病率，以及任何原因导致的死亡。
