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比例，并增加了糖尿病和心血管死亡的风险。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。虽然动脉粥样硬化的常规危险因素在代谢综合征中的心血管疾病的发病机制中起重要作用，但葡萄糖、胰岛素、炎性细胞因子和生长因子的增加;肾素-血管紧张素-醛固酮系统活性的增加;以及内皮功能障碍都导致代谢综合征中纤溶功能受损。在动物模型和临床试验中，阻断肾素-血管紧张素-醛固酮系统可改善纤溶平衡，降低2型糖尿病的发病率，并预防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实验室的数据，这些数据表明内源性一氧化氮通过鸟苷3 '，5'-环一磷酸（cGMP）依赖性机制促进血管紧张素转换酶（ACE）抑制对纤溶平衡和胰岛素敏感性的有利影响，而一氧化氮似乎通过cGMP非依赖性机制调节内皮细胞的刺激胞吐作用。同时，ACE抑制和增加cGMP的药理学策略在动物模型中改善胰岛素敏感性和肌肉葡萄糖摄取。基于这些数据，我们提出测试中心假设，增加cGMP，或者通过施用药理学一氧化氮供体（具体目标1和3）或通过给予磷酸二酯酶抑制剂防止其降解（特定目的2和3）将增强ACE抑制对纤溶平衡的有利影响（主要假设）和胰岛素敏感性（次要假设）在代谢综合征的个人。这些研究有望产生新的药理学策略，以减少糖尿病的患病率和死亡率，由于血栓性心血管事件的代谢综合征。

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.