Cook Stéphane
Swiss Cardiovascular Centre, Bern, Switzerland.
Swiss Med Wkly. 2006 Feb 18;136(7-8):103-13. doi: 10.4414/smw.2006.11068.
Prevention of coronary artery disease (CAD) and reduction of its mortality and morbidity remains a major public health challenge throughout the "Western world". Recent evidence supports the concept that the impairment of endothelial function, a hallmark of insulin resistance states, is an upstream event in the pathophysiology of insulin resistance and its main corollaries: atherosclerosis and myocardial infarction. Atherosclerosis is currently thought to be the consequence of a subtle imbalance between pro- and anti-oxidants that produces favourable conditions for lesion progression towards acute thrombotic complications and clinical events. Over the last decade, a remarkable burst of evidence has accumulated, offering the new perspective that bioavailable nitric oxide (NO) plays a pivotal role throughout the CAD-spectrum, from its genesis to the outcome after acute events. Vascular NO is a critical modulator of coronary blood flow by inhibiting smooth muscle contraction and platelet aggregation. It also acts in angiogenesis and cytoprotection. Defective endothelial nitric oxide synthase (eNOS) driven NO synthesis causes development of major cardiovascular risk factors (insulin resistance, arterial hypertension and dyslipidaemia) in mice, and characterises CAD-prone insulin-resistant humans. On the other hand, stimulation of inducible nitric oxide synthase (iNOS) and NO overproduction causes metabolic insulin resistance and characterises atherosclerosis, heart failure and cardiogenic shock in humans, suggesting a "Yin-Yang" effect of NO in the cardiovascular homeostasis. Here, we will present a concise overview of the evidence for this novel concept, providing the conceptual framework for developing a potential therapeutic strategy to prevent and treat CAD.
在整个“西方世界”，预防冠状动脉疾病（CAD）并降低其死亡率和发病率仍然是一项重大的公共卫生挑战。最近的证据支持这样一种观点，即内皮功能受损作为胰岛素抵抗状态的一个标志，是胰岛素抵抗及其主要后果（动脉粥样硬化和心肌梗死）病理生理学中的一个上游事件。目前认为动脉粥样硬化是促氧化剂和抗氧化剂之间微妙失衡的结果，这种失衡为病变发展为急性血栓并发症和临床事件创造了有利条件。在过去十年中，积累了大量显著的证据，提供了一个新的视角，即生物可利用的一氧化氮（NO）在CAD的整个病程中，从其发生到急性事件后的结局，都起着关键作用。血管NO通过抑制平滑肌收缩和血小板聚集，是冠状动脉血流的关键调节因子。它还在血管生成和细胞保护中发挥作用。由内皮型一氧化氮合酶（eNOS）驱动的NO合成缺陷会导致小鼠出现主要的心血管危险因素（胰岛素抵抗、动脉高血压和血脂异常），并是易患CAD的胰岛素抵抗人群的特征。另一方面，诱导型一氧化氮合酶（iNOS）的刺激和NO的过量产生会导致代谢性胰岛素抵抗，并是人类动脉粥样硬化、心力衰竭和心源性休克的特征，这表明NO在心血管稳态中具有“阴阳”效应。在此，我们将简要概述这一新概念的证据，为制定预防和治疗CAD的潜在治疗策略提供概念框架。
