DIRECT EFFECTS OF ANTIRETROVIRAL THERAPY ON CARDIAC ENERGY HOMEOSTASIS

描述（由申请人提供）：该项目的长期目标是表征抗逆转录病毒治疗对心肌能量稳态的影响，并阐明这些底物递送的变化如何对应激心脏的心功能产生不利影响。本研究旨在确定HIV蛋白酶抑制剂（PIs）对合并心肌应激或损伤的心功能的直接影响，确定导致这些变化的分子机制，并提供有效的治疗策略来预防或改善心功能障碍。我们假设，在急性和慢性应激的情况下，药物引起的正常底物递送和/或利用的改变损害了收缩功能，导致发病率和死亡率增加。我们进一步假设，增加心肌葡萄糖摄取的能力将改善心功能和生存。为了验证这些假设，将在扩张型心肌病和心肌梗死的小鼠模型中测试PIs对心功能和生存的影响。PIs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钙通量的能力将在体外和离体工作心脏模型系统中进行研究。最后，将测试肠促胰岛素模拟艾塞那肽改善pi治疗小鼠胰岛素敏感性和延长生存期的能力。综上所述，这些研究将为抗逆转录病毒治疗对心脏相关发病率和死亡率的直接贡献提供新的见解，并将为努力改善心血管疾病发展风险增加的艾滋病毒感染者的生活质量提供理论基础。公共卫生相关性：已知用于治疗艾滋病毒感染患者的药物会导致胰岛素抵抗和糖尿病的发生，同时还会导致其他变化，大大增加患心脏病的风险。虽然这些药物直接改变心脏功能的能力以前没有研究过，但最近的临床试验显示，在试图减少治疗相关并发症的间歇性治疗中断的患者中，心脏相关不良事件的发生率意外增加。由于艾滋病毒感染已经从一种致命疾病转变为一种慢性疾病，预计在未来几十年里，治疗这一老龄化人口的医疗保健费用将急剧增加。这项研究将对HIV治疗对心脏胰岛素抵抗的直接影响有更深入的了解，并将为预防和/或治疗HIV心脏异常提供基本的策略。这项研究还具有显著的潜力，可以改善在更广泛的2型糖尿病背景下心脏病的预防和治疗。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The medications used in the treatment of HIV-infected patients are known to contribute to the development of insulin resistance and diabetes, together with other changes that greatly increase the risk of heart disease. While the ability of these drugs to directly alter heart function has not been previously studied, recent clinical trials have shown an unexpected increase in adverse heart-related events in patients who have had intermittent treatment interruptions in an attempt to reduce treatment-related complications. Since HIV infection has transitioned from a fatal to a chronic disease, the health care costs for treating this aging population are predicted to increase dramatically in the coming decades. This research will generate a greater understanding of the direct effects of HIV therapies on insulin resistance in the heart and will provide rationale strategies to prevent and/or treat heart abnormalities in HIV. This research also has significant potential to improve the prevention and treatment of heart disease in the wider context of type 2 diabetes.