Juhan-Vague I, Collen D
Laboratoire d'Hématologie, Centre Hospitalier Universitaire, Hôpital de la Timone, Marseille, France.
Ann Epidemiol. 1992 Jul;2(4):427-38. doi: 10.1016/1047-2797(92)90092-5.
Atherosclerosis is probably caused by multiple interacting factors such as disturbed lipid metabolism; endothelial cell damage, leading to platelet aggregation and monocyte invasion with the release of mitogenic factors; and disorders of fibrin balance, leading to persisting fibrin deposits. Deficient fibrinolysis may (1) predispose to fibrin deposition and contribute to the pathogenesis of atherosclerosis and (2) contribute to occlusive thrombus formation on fissured plaque, provoking atherothrombosis. Prospective epidemiologic studies have so far not provided definitive evidence that deficient fibrinolysis constitutes a significant risk factor for the development of atherosclerosis. Two recent findings, however, strongly suggest a contribution: (1) Increased lipoprotein(a) levels that reduce tissue-type plasminogen activator (t-PA)-mediated clot lysis are a clear risk factor for atherosclerosis; and (2) increased plasminogen activator inhibitor-1 (PAI-1) levels in patients with disturbed glucose tolerance predispose to an accelerated development of atherosclerotic disease. However, deficient fibrinolysis constitutes a risk factor for the development of thrombotic complications (acute myocardial infarction) in patients with coronary artery disease. The potential role of deficient fibrinolysis in the pathogenesis of atherosclerosis and of atherothrombosis suggests that drugs normalizing deficient endogenous fibrinolysis by either reducing PAI-1 synthesis or by stimulating endogenous t-PA synthesis may be of clinical value. Although regulation of the gene expression of PAI-1 and t-PA is presently under active investigation, no potent specific and safe agents to downregulate PAI-1 or to upregulate t-PA have as yet been identified. Retinoic acid appears to be a specific inducer of t-PA synthesis in human endothelial cells in culture and may constitute a model for the development of drugs that stimulate endogenous t-PA synthesis.
动脉粥样硬化可能由多种相互作用的因素引起，如脂质代谢紊乱；内皮细胞损伤，导致血小板聚集和单核细胞浸润，并释放促有丝分裂因子；以及纤维蛋白平衡失调，导致纤维蛋白持续沉积。纤维蛋白溶解功能不足可能（1）易导致纤维蛋白沉积，促进动脉粥样硬化的发病机制，（2）促进裂隙斑块上形成闭塞性血栓，引发动脉粥样硬化血栓形成。前瞻性流行病学研究迄今尚未提供确凿证据表明纤维蛋白溶解功能不足是动脉粥样硬化发展的重要危险因素。然而，最近的两项发现有力地表明了其作用：（1）脂蛋白（a）水平升高会降低组织型纤溶酶原激活物（t-PA）介导的血凝块溶解，这是动脉粥样硬化的明确危险因素；（2）糖耐量异常患者中纤溶酶原激活物抑制剂-1（PAI-1）水平升高易导致动脉粥样硬化疾病加速发展。然而，纤维蛋白溶解功能不足是冠状动脉疾病患者发生血栓并发症（急性心肌梗死）的危险因素。纤维蛋白溶解功能不足在动脉粥样硬化和动脉粥样硬化血栓形成发病机制中的潜在作用表明，通过减少PAI-1合成或刺激内源性t-PA合成来使内源性纤维蛋白溶解功能不足正常化的药物可能具有临床价值。尽管目前正在积极研究PAI-1和t-PA的基因表达调控，但尚未确定有效、特异且安全的下调PAI-1或上调t-PA的药物。视黄酸似乎是培养的人内皮细胞中t-PA合成的特异性诱导剂，可能构成刺激内源性t-PA合成药物开发的模型。
