Protection by Thiazolidinediones in Myocardial Ischemia

噻唑烷二酮类药物对心肌缺血的保护作用

• 批准号: 6436621
• 负责人: GREGORY G SCHWARTZ
• 金额: $ 28.35万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-02-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6436621
• 关键词: bioenergetics; carbohydrate metabolism; cytoprotection; glucose transport; glucose transporter; heart disorder chemotherapy; heart function; heart metabolism; hypoglycemic agents; insulin sensitivity /resistance; myocardial infarct sizing; myocardial ischemia /hypoxia; nonhuman therapy evaluation; oxidative phosphorylation; oxidative stress; peroxisome proliferator activated receptor; pharmacokinetics; receptor expression; swine; troglitazone; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Thiazolidinediones are ligands of the peroxisome proliferator associated receptor (PPAR)-gamma, a key orchestrator of cellular energy substrate metabolism. Thiazolidinediones are used clinically to treat Type II diabetes. This laboratory has demonstrated that chronic treatment of normal, non-diabetic pigs with a thiazolidinedione drug improves recovery of left ventricular function after ischemia and reperfusion in vivo. This project will test the hypothesis that thiazolidinediones improve recovery of cardiac function after ischemia and reduce myocardial infarct size through specific alterations of myocardial gene expression and energy substrate metabolism that are coupled to PPAR-gamma activation. In particular, it is hypothesized that chronic thiazolidinedione treatment of non-diabetic pigs improves recovery of cardiac function after ischemia and reperfusion by: 1. Increasing myocardial expression of glucose transporters GLUT1 and GLUT4, thereby facilitating glucose uptake and enhancing myocardial insulin sensitivity 2. Increasing the oxidation of carbohydrate substrates in reperfused myocardium 3. Increasing myocardial expression of uncoupling protein-2, which may serve to mitigate oxidant injury during reperfusion 4. Decreasing myocardial expression of pro-inflammatory and negative inotropic cytokines, such as tumor necrosis factor-alpha If the proposed studies confirm these salutary effects of PPAR-gamma activation with thiazolidinediones, the results may suggest an important new treatment strategy for patients with ischemic heart disease, even those without diabetes.

描述（由申请人提供）： 噻唑烷二酮类是以下配体 过氧化物酶体增殖物相关受体（PPAR）-γ，是 细胞能量底物代谢。噻唑烷二酮类药物临床上用于 治疗 II 型糖尿病。该实验室已证明慢性治疗 使用噻唑烷二酮药物改善正常非糖尿病猪的恢复 体内缺血和再灌注后的左心室功能。 该项目将测试噻唑烷二酮类药物可改善恢复的假设 缺血后的心脏功能并减少心肌梗死面积 心肌基因表达和能量底物的特异性改变 与 PPAR-γ 激活相关的代谢。特别是，它是 假设对非糖尿病猪进行长期噻唑烷二酮治疗 通过以下方式改善缺血和再灌注后心脏功能的恢复： 1.增加心肌葡萄糖转运蛋白GLUT1和GLUT4的表达， 从而促进葡萄糖摄取并增强心肌胰岛素 灵敏度 2. 增加再灌注心肌中碳水化合物底物的氧化 3. 增加心肌解偶联蛋白2的表达，这可能有助于 减轻再灌注过程中的氧化损伤 4. 减少促炎和负性肌力的心肌表达 细胞因子，例如肿瘤坏死因子-α 如果拟议的研究证实 PPAR-gamma 激活的这些有益作用 对于噻唑烷二酮类药物，结果可能表明一种重要的新治疗方法 针对缺血性心脏病患者（甚至没有糖尿病的患者）的策略。