DIRECT EFFECTS OF ANTIRETROVIRAL THERAPY ON CARDIAC ENERGY HOMEOSTASIS

抗逆转录病毒治疗对心脏能量稳态的直接影响

• 批准号: 8079125
• 负责人: PAUL W HRUZ
• 金额: $ 38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079125
• 关键词: Acute; Adult; Affect; Age; Animals; Atazanavir; Biological Models; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cell Fractionation; Cell membrane; Chronic; Chronic Disease; Chronic stress; Clinical Trials; Congenital Heart Defects; Defect; Deoxyglucose; Development; Diabetes Mellitus; Dilated Cardiomyopathy; Energy Metabolism; Event; Exhibits; Exposure to; Fractionation; Functional disorder; GLUT4 gene; Glucose; Glucose Transporter; Goals; HIV; HIV Infections; HIV Protease Inhibitors; HIV therapy; Harvest; Health; Health Care Costs; Heart; Heart Diseases; Heart failure; Homeostasis; Immunofluorescence Microscopy; In Situ; In Vitro; Individual; Infarction; Injury; Insulin Resistance; Interruption; Lead; Left; Lopinavir/Ritonavir; Measures; Metabolic; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Nucleosides; Patients; Pharmaceutical Preparations; Phosphorylation; Prevention; Protease Inhibitor; Quality of life; Research; Reverse Transcriptase Inhibitors; Risk; SLC2A1 gene; Stress; Testing; Therapeutic; Ventricular; Western Blotting; Work; acute stress; aging population; antiretroviral therapy; base; detection of nutrient; exenatide; fatty acid metabolism; glucagon-like peptide 1; glucose transport; glucose uptake; heart disease risk; heart function; improved; in vivo; injured; insight; insulin sensitivity; insulin signaling; lifetime risk; mimetics; mortality; novel therapeutic intervention; prevent; protein distribution; release of sequestered calcium ion into cytoplasm; uptake

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.

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疗法对心肌稳态的影响，并阐明底物递送的这些变化如何对压力心脏中的心脏功能不利影响。该提案中的研究旨在建立HIV蛋白酶抑制剂（PI）在随之而来的心肌应激或损伤的情况下对心脏功能的直接影响，以确定对这些变化负责的分子机制，并提供有效的治疗策略以预防或减轻心脏功能障碍。我们假设药物诱导的急性和慢性应激障碍障碍的正常底物递送和/或利用的改变，从而增加了发病率和死亡率。我们进一步假设，增加心肌葡萄糖摄取的能力将改善心脏功能和生存。为了检验这些假设，PI对心肌病和心肌梗死的鼠模型中的心脏功能和生存的影响将测试。 PI影响营养感应，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孤立的工作心脏模型系统中进行研究。最后，将测试肠降直直染素模拟核酸酯提高胰岛素敏感性和延长PI-PI-治疗小鼠的生存率的能力。综上所述，这些研究将提供有关抗逆转录病毒疗法对心脏有关的发病率和死亡率的直接贡献的新见解，并将为改善艾滋病毒感染者的生活质量的努力提供理由基础，该艾滋病毒感染者的心血管疾病风险增加了。公共卫生相关性：已知用于治疗艾滋病毒感染患者的药物有助于胰岛素抵抗和糖尿病的发展，以及其他变化大大增加了心脏病的风险。尽管这些药物直接改变心脏功能的能力尚未进行过研究，但最近的临床试验表明，患有间歇性治疗中断的患者的不良心脏相关事件意外增加，以减少与治疗相关的并发症。由于HIV感染已从致命转变为慢性疾病，因此预计在未来几十年中，治疗这种老龄化人群的医疗保健费用将大大增加。这项研究将对艾滋病毒疗法对心脏胰岛素抵抗的直接影响产生更深入的了解，并将提供预防和/或治疗艾滋病毒心脏异常的基本原理策略。这项研究在2型糖尿病的更广泛情况下还具有改善心脏病的预防和治疗的巨大潜力。