Renin-Angiotensin and Fibrinolysis Interaction in Humans

描述（由申请人提供）：肥胖和代谢综合征的患病率在发达国家已达到流行病的程度，并传达了糖尿病和心血管死亡的风险增加。即使在发展为显性糖尿病之前，患有代谢综合征的个体也更有可能死于心血管疾病。而动脉粥样硬化的传统危险因素在代谢综合征中心血管疾病的发病机制中发挥重要作用，血糖、胰岛素、炎症细胞因子和生长因子升高；肾素-血管紧张素-醛固酮系统活性增加；内皮功能障碍都会导致代谢综合征的纤溶功能受损。在动物模型和临床试验中，肾素-血管紧张素-醛固酮系统的中断改善了纤溶平衡，降低了2型糖尿病的发病率，并预防了代谢综合征患者的心血管事件。最近的临床试验数据表明，在中断肾素-血管紧张素-醛固酮系统的药物背景下给予一氧化氮供体也可降低心血管死亡率。目前的建议来自于我们实验室和其他人的数据，这些数据表明内源性一氧化氮通过鸟苷3',5'-环单磷酸（cGMP）依赖机制促进血管紧张素转换酶（ACE）抑制对纤维蛋白溶解平衡和胰岛素敏感性的有利作用，而一氧化氮似乎通过cGMP独立机制调节内皮细胞受刺激的胞外分泌。同时，ACE抑制和增加cGMP的药理学操作均可改善动物模型中的胰岛素敏感性和肌肉葡萄糖摄取。基于这些数据，我们建议验证中心假设，即通过给药一氧化氮供体（SPECIFIC AIMS 1和3）增加cGMP的形成，或通过给药磷酸二酯酶抑制剂（SPECIFIC AIMS 2和3）防止其降解，增加cGMP，可以增强ACE抑制对代谢综合征患者纤溶平衡（主要假设）和胰岛素敏感性（次要假设）的有利作用。这些研究有望产生新的药理学策略，以降低代谢综合征中血栓性心血管事件引起的糖尿病患病率和死亡率。

DESCRIPTION (provided by applicant): The prevalence of obesity and the metabolic syndrome has reached epidemic proportions in developed countries and conveys an increased risk of diabetes and cardiovascular mortality. Even before the development of overt diabetes, individuals with the metabolic syndrome are more likely to die of cardiovascular disease. While conventional risk factors for atherosclerosis play an important role in the pathogenesis of cardiovascular disease in the metabolic syndrome, increased glucose, insulin, inflammatory cytokines, and growth factors; increased activity of the renin-angiotensin-aldosterone system; and endothelial dysfunction all lead to impaired fibrinolytic function in the metabolic syndrome. Interruption of the renin-angiotensin-aldosterone system improves fibrinolytic balance, decreases the incidence of type 2 diabetes in both animal models and clinical trials, and prevents cardiovascular events in individuals with the metabolic syndrome. Recent clinical trial data suggest that administration of a nitric oxide donor also reduces cardiovascular mortality when given on a background of drugs that interrupt the renin-angiotensin- aldosterone system. The current proposal derives from data from our laboratory and others that indicate that endogenous nitric oxide contributes to the favorable effects of angiotensin-converting enzyme (ACE) inhibition on fibrinolytic balance and insulin sensitivity through guanosine 3',5'-cyclic monophosphate (cGMP)-dependent mechanism(s), whereas nitric oxide appears to modulate stimulated exocytosis from endothelial cells through a cGMP-independent mechanism. At the same time, both ACE inhibition and pharmacologic maneuvers to increase cGMP improve insulin sensitivity and muscle glucose uptake in animal models. Based on these data we propose to test the central hypothesis that increasing cGMP, either by increasing its formation by administering a pharmacologic nitric oxide donor (SPECIFIC AIMS 1 and 3) or by preventing its degradation by administering a phosphodiesterase inhibitor (SPECIFIC AIMS 2 and 3) will enhance the favorable effects of ACE inhibition on fibrinolytic balance (primary hypothesis) and insulin sensitivity (secondary hypothesis) in individuals with the metabolic syndrome. These studies promise to yield novel pharmacological strategies to decrease the prevalence of diabetes and mortality due to thrombotic cardiovascular events in the metabolic syndrome.