ENDOTHELIAL DYSFUNCTION IN CORONARY ATHEROSCLEROSIS

作为一名对心肌梗塞的基本机制感兴趣的心脏病专家 缺血，我的主要职业目标是了解 内皮功能紊乱在动脉粥样硬化中的作用及其机制 导致血管舒缩张力异常和血栓形成。我的 细胞生物学和临床研究的双重训练使我处于一种 在这方面处于有利地位，因为很少有心脏病专家 培养了必要的技能，以应用源自 心血管疾病患者的血管生物学。这 在我职业生涯的关键时刻，我完成了我的职业生涯 向完全独立的研究状态过渡。为这一蓬勃发展的 有兴趣缩小基础研究和临床研究之间的差距 继续发展将需要良好的结构和保护时间。这个 制度环境将有利于这一职业发展战略。 如果我的工资支持来自研究来源，我的发展。 这里提供的研究重点是定义存在如何 对冠状动脉粥样硬化患者的影响 内皮依赖性血管扩张剂和血管收缩反应。一个 提出了一项研究计划，利用来自 实验实验室要解决三个具体目标。第一个遗嘱 检验人类内皮血管扩张剂功能障碍的假说 冠状动脉导致缩窄性高反应性 儿茶酚胺。第二个具体目标将检验这一假设 血管内皮源性收缩因子(多肽内皮素，AS 以及前列腺素类因子)是从人类动脉粥样硬化中分泌出来的 动脉对已知的刺激有不适当的大量反应 导致血管收缩增强，从而促进发展 心肌缺血的症状。第三个具体目标将在患者身上进行检查 从实验研究中得出的概念是积极的降低 胆固醇可以改善内皮依赖的血管功能 血管管腔大小的重要变化。这些研究应该 扩大对异常的发病机制和治疗的认识 收缩人类冠状动脉，并促进临床尝试 控制活动性脑缺血。

As a cardiologist interested in the basic mechanisms of myocardial ischemia, my primary career objective is to gain an understanding of the role of disturbed endothelial function in atherosclerosis and how it contributes to abnormalities of vasomotor tone and to thrombosis. My dual training in cell biology and clinical research places me in an advantageous position in this regard, since few cardiologists have developed the necessary skills to apply new insights derived from vascular biology to patients with cardiovascular diseases. This application comes at a crucial point in my career as I complete my transition toward fully independent research status. For this burgeoning interest in closing the gap between basic and clinical research to continue to evolve will require well structured and protected time. The institutional environment will be conducive to this strategy for career development provided that my salary support comes from research sources. The studies presented here focus on defining how the presence of atherosclerosis in the coronary arteries of patients effects endothelium-dependent vasodilator and vasoconstrictor responses. A program of research is proposed that utilizes new insights from the experimental laboratory to address three specific aims. The first will test the hypothesis that endothelial vasodilator dysfunction in human coronary arteries leads to constrictor hyperresponsiveness to catecholamines. The second specific aim will test the hypothesis that endothelium-derived constrictor factors (the polypeptide endothelin, as well as prostanoid factors) are secreted from human atherosclerotic arteries in inappropriately large amounts in response to stimuli known to cause enhanced vasoconstriction and thereby contribute to the development of myocardial ischemia. The third specific aim will examine in patients the concepts derived from experimental studies that aggressive lowering of cholesterol can improve endothelium-dependent vascular function apart from important changes in vessel luminal size. These studies should expand our knowledge of the mechanisms and treatment of abnormal constriction of human coronary arteries, and facilitate clinical attempts to control active ischemia.