Role of Vascular NADH/NAPDH oxidase in atherogenesis

活性氧（ROS）诱导的氧化应激参与多种血管疾病的发病机制，包括动脉粥样硬化和冠状动脉疾病。NADH/NADPH氧化酶是活性氧（ROS）的重要来源。最近，我们发现p22^<phox>是这种氧化酶的重要组成部分，在人类冠状动脉中表达，并且随着动脉粥样硬化的进展其表达增强。本研究旨在探讨NADH/NADPH氧化酶在多种血管疾病发病机制中的功能重要性。我们检测了溶血磷脂酰胆碱（LPC），氧化LDL的致动脉粥样硬化成分，对培养内皮细胞中NADH/NADPH氧化酶活性的影响。培养的主动脉内皮细胞匀浆具有NADH/NADPH酶活性。LPC诱导o_2生成。因此内皮细胞中o_2的产生主要是由NADH/NADPH氧化酶系统介导的，LPC激活该氧化酶促进o_2的产生。研究了NADH/NADPH氧化酶在动脉粥样硬化性冠心病发病过程中的功能作用。为此，我们检测了定向冠状动脉粥样硬化切除术（DCA）标本中p22^<phox>的表达、氧化LDL的分布和ROS的产生。DCA标本取自稳定型（SAP）或不稳定型心绞痛（UAP）患者。ROS的产生与p22^<phox>和氧化LDL的分布密切相关。ROS与p22^<phox>或氧化LDL的表达有相关性。p22^<pfox b>基NADH/NADPH氧化酶产生的ROS可能介导LDL的氧化修饰，可能在动脉粥样硬化性冠状动脉疾病的发病机制中起重要作用。

Oxidative stress induced by reactive oxygen species (ROS) is implicated in the pathogenesis of a variety of vascular diseases including atherosclerosis and coronary artery disease. NADH/NADPH oxidase is an important source of reactive oxygen species (ROS).Recently, we demonstrated that p22^<phox>, an essential component of this oxidase, was expressed in human coronary arteries, and its expression was enhanced with the progression of atherosclerosis. The present study was undertaken to investigate the functional importance of NADH/NADPH oxidase in pathogenesis of various vascular diseases.We examined the effect of lysophosphatidylcholine (LPC), atherogenic component of oxidized LDL, on the activity of NADH/NADPH oxidase in cultured endthelial cells. Homogenates of cultured aortic endothelial cell had the enzymatic activity of NADH/NADPH. LPC induced O_2-generation. Thus the production of O_2-in endothelial cells is mainly mediated by the NADH/NADPH oxidase system and LPC activates this oxidase to enhance O_2-production.The functional role of NADH/NADPH oxidase in pathpgenesis of atherosclerotic corbriary disease was investigated. For this aim, the expression of p22^<phox>, distribution of oxidized LDL and generation of ROS in directional coronary atherectomy (DCA) specimens were examined. DCA specimens were obtained from patients with stable (SAP) or unstable angina pectoris (UAP). ROS generation was closely associated, with the distribution of p22^<phox> and oxidized LDL. There was a correlation between ROS and the expression of p22^<phox> or oxidized LDL. These factors of UAP were significantly higher compared with SAP. ROS generated by p22^<pfox> -based NADH/NADPH oxidase likely mediate oxidative modification of LDL, and it might play a major role in pathogenesis of atherosclerotic coronary artery disease.