Keidar S
Lipid Research Laboratory, Rambam Medical Center, Rappaport Institute for Research in the Medical Sciences and The Bruce Rappaport Technion Faculty of Medicine, Haifa, Israel.
Life Sci. 1998;63(1):1-11. doi: 10.1016/s0024-3205(98)00014-9.
Hypertension is a known risk factor for the development of atherosclerosis. However, in most of the studies, no effect of blood pressure reduction was demonstrated on the incidence of coronary artery disease, except in the SHEP study in which it was shown that in older persons, with isolated systolic hypertension, antihypertensive stepped-care drug treatment reduced the incidence of total stroke and major cardiovascular event. In hypertensive patients with elevated plasma renin activity, a 5-fold increased incidence of myocardial infarction was demonstrated. As oxidation of low density lipoprotein (LDL) was suggested to be a major risk factor for atherosclerosis, we studied the relationship between hypertension and LDL oxidation. We demonstrated increased propensity of LDL obtained from hypertensive patients to oxidative modification, in comparison with LDL obtained from normotensive subjects and suggested that angiotensin II (Ang-II) may be involved in this effect. Ang-II was shown to enhance macrophage lipid peroxidation both in vivo and in vitro. This effect was dose-dependent and involved the binding of Ang-II to its receptor on the macrophage surface. In addition, these lipid peroxidized Ang-II-treated macrophages could substantially oxidize LDL. Ang-II was shown to possess additional atherogenic properties such as increasing the activity of the macrophage oxidized LDL receptors. It also binds to LDL, thus leading to the formation of a modified lipoprotein, which is taken up by macrophages at enhanced rate through the scavenger receptor. Inhibition of Ang-II formation by angiotensin converting enzyme inhibitors reduced LDL peroxidation in hypertensive patients as well as in the atherosclerotic apo E deficient mice. The reduction in LDL peroxidation in these mice was accompanied by a 70-90% reduction in the atherosclerotic lesion area. A similar effect in these mice was demonstrated with the Ang-II receptor antagonist, Losartan. Thus, we suggest that Ang-II is involved in the development of atherogenesis in hypertensive patients and inhibition of Ang-II formation or prevention of its interaction with its receptor may attenuate the atherosclerotic process.
高血压是动脉粥样硬化发展的已知危险因素。然而，在大多数研究中，未证明血压降低对冠心病发病率有影响，除了收缩期高血压计划（SHEP）研究，该研究表明，在患有单纯收缩期高血压的老年人中，降压阶梯式药物治疗可降低总中风和主要心血管事件的发病率。在血浆肾素活性升高的高血压患者中，心肌梗死的发病率增加了5倍。由于低密度脂蛋白（LDL）氧化被认为是动脉粥样硬化的主要危险因素，我们研究了高血压与LDL氧化之间的关系。我们证明，与正常血压受试者获得的LDL相比，高血压患者获得的LDL氧化修饰倾向增加，并提示血管紧张素II（Ang-II）可能参与了这一效应。Ang-II在体内和体外均显示可增强巨噬细胞脂质过氧化。这种效应是剂量依赖性的，涉及Ang-II与其在巨噬细胞表面的受体结合。此外，这些经脂质过氧化的Ang-II处理的巨噬细胞可大量氧化LDL。Ang-II还具有其他致动脉粥样硬化特性，如增加巨噬细胞氧化LDL受体的活性。它还与LDL结合，从而导致形成一种修饰的脂蛋白，巨噬细胞通过清道夫受体以更快的速率摄取这种脂蛋白。血管紧张素转换酶抑制剂抑制Ang-II的形成可降低高血压患者以及动脉粥样硬化载脂蛋白E缺陷小鼠的LDL过氧化。这些小鼠LDL过氧化的降低伴随着动脉粥样硬化病变面积减少70-90%。血管紧张素II受体拮抗剂氯沙坦在这些小鼠中也显示出类似的效果。因此，我们认为Ang-II参与了高血压患者动脉粥样硬化的发展，抑制Ang-II的形成或阻止其与受体的相互作用可能会减弱动脉粥样硬化进程。
