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疗法对心肌细胞的影响， 能量稳态，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 在紧张的心脏。本提案中的研究旨在确定HIV蛋白酶的直接作用 抑制剂（PI）对心脏功能的影响，在伴随心肌应激或损伤的情况下， 负责这些变化的分子机制，并提供有效的治疗策略 以预防或改善心脏功能障碍。我们假设药物引起的正常底物变化 在急性和慢性应激环境中的递送和/或利用损害收缩功能，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 将在扩张型心肌病和心肌梗塞的鼠模型中测试功能和存活率。的 PI影响营养感知、改变胰岛素信号传导、损害葡萄糖摄取和改变心肌 将在体外和在分离的工作心脏模型系统中研究钙通量。最后，能力 肠降血糖素模拟物exengland改善胰岛素敏感性和延长PI治疗小鼠的生存期， 测试.总之，这些研究将为抗逆转录病毒药物的直接作用提供新的见解。 治疗心脏相关的发病率和死亡率，并将提供一个合理的基础，努力改善 生活质量的艾滋病毒感染者的心血管疾病的发展风险增加。

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.