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）：本项目的长期目标是描述抗逆转录病毒治疗对心肌能量稳态的影响，并阐明底物输送的这些变化如何对应激心脏的心脏功能产生不利影响。本提案中的研究旨在确定HIV蛋白酶抑制剂（PI）在伴随心肌应激或损伤的情况下对心脏功能的直接影响，以确定导致这些变化的分子机制，并提供预防或改善心功能不全的有效治疗策略。我们推测，药物诱导的改变正常底物的交付和/或利用的设置中的急性和慢性应激损害收缩功能，导致发病率和死亡率增加。我们进一步假设，增加心肌葡萄糖摄入的能力将改善心脏功能和生存率。为了检验这些假设，将在扩张型心肌病和心肌梗死的鼠模型中检验PI对心脏功能和存活率的影响。将在体外和分离的工作心脏模型系统中研究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钙通量的能力。最后，将测试肠降血糖素模拟物艾塞那肽在PI处理的小鼠中改善胰岛素敏感性和延长存活的能力。总之，这些研究将提供关于抗逆转录病毒治疗对心脏病相关发病率和死亡率的直接贡献的新见解，并将为努力改善心血管疾病风险增加的HIV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有助于胰岛素抵抗和糖尿病的发展，以及大大增加心脏病风险的其他变化。虽然这些药物直接改变心脏功能的能力以前没有研究过，但最近的临床试验表明，为了减少治疗相关并发症而间歇性中断治疗的患者的不良心脏相关事件意外增加。由于艾滋病毒感染已从致命疾病转变为慢性疾病，预计在未来几十年内，治疗这一老龄化人口的医疗保健费用将大幅增加。这项研究将使人们更好地了解艾滋病毒治疗对心脏胰岛素抵抗的直接影响，并将为预防和/或治疗艾滋病毒心脏异常提供合理的策略。这项研究还具有在更广泛的2型糖尿病背景下改善心脏病预防和治疗的巨大潜力。