DIRECT EFFECTS OF ANTIRETROVIRAL THERAPY ON CARDIAC ENERGY HOMEOSTASIS

项目摘要 该项目的长期目标是描述抗逆转录病毒治疗对心肌的影响。 能量平衡，并阐明这些底物输送的变化如何对心脏功能产生不利影响 在紧张的心里。这项提案中的研究旨在确定艾滋病毒蛋白酶的直接影响。 在伴随心肌应激或损伤的情况下，抑制物(PI)对心功能的影响，以确定 分子机制(S)，负责这些变化，并提供有效的治疗策略 预防或改善心脏功能不全。我们假设药物引起的正常底物的改变 在急性和慢性应激环境下的交付和/或利用会损害收缩功能，导致 发病率和死亡率增加。我们进一步假设，增加心肌葡萄糖的能力 摄取将改善心脏功能和存活率。为了验证这些假设，PI对心脏的影响 功能和存活率将在扩张型心肌病和心肌梗死的小鼠模型中进行测试。这个 PI影响营养感知、改变胰岛素信号、损害葡萄糖摄取和改变心肌细胞的能力 钙通量将在体外和隔离的工作心脏模型系统中进行研究。最后，能力 胰岛素类似物埃塞那肽改善胰岛素敏感性和延长PI治疗小鼠生存时间的研究将是 测试过。总之，这些研究将为抗逆转录病毒的直接贡献提供新的见解。 治疗心脏相关的发病率和死亡率，并将为努力改善 艾滋病毒感染者患心血管疾病风险增加的生活质量。

Project Summary The long-term goals of this project are to characterize the influence of antiretroviral therapies on myocardial energy homeostasis and to elucidate how these changes in substrate delivery adversely affect cardiac function in the stressed heart. The studies in this proposal are intended to establish direct effects of HIV protease inhibitors (PIs) on heart function in the setting of concomitant myocardial stress or injury, to identify the molecular mechanism(s) that are responsible for these changes, and to provide effective therapeutic strategies to prevent or ameliorate cardiac dysfunction. We hypothesize that drug-induced alterations in normal substrate delivery and/or utilization in the setting of acute and chronic stress impair contractile function, resulting in increased morbidity and mortality. We further hypothesize that the ability to increase myocardial glucose uptake will improve cardiac function and survival. To test these hypotheses, the effects of PIs on cardiac function and survival will be tested in murine models of dilated cardiomyopathy and myocardial infarction. The ability of PIs to affect nutrient sensing, alter insulin signaling, impair glucose uptake, and change myocardial calcium flux will be investigated both in vitro and in an isolated working heart model system. Finally, the ability of the incretin mimetic exenatide to improve insulin sensitivity and prolong survival in PI-treated mice will be tested. Taken together, these studies will provide new insights regarding the direct contribution of antiretroviral therapy to cardiac-related morbidity and mortality and will provide a rationale basis for efforts to improve the quality of life of HIV infected individuals at increased risk for the development of cardiovascular disease.