COCAINE AND CARDIOVASCULAR DYSFUNCTION IN MURINE AIDS

可卡因滥用和HIV感染的结合是临床医生和研究人员面临的一个新问题和独特的挑战。两者都只与心血管并发症有关，包括急性事件(心绞痛、心律失常、心肌梗死)和慢性疾病(心肌炎、血管病、心肌病、充血性心力衰竭)，但涉及的机制尚不清楚，治疗策略尚未优化。由于它们经常共存，因此评估它们组合的病理生理后果是合理的。在这项建议中，我们的主要目标是确定可卡因引起心血管功能障碍的机制，并利用已建立的相关动物模型(小鼠艾滋病、LPBM5感染)确定可卡因在逆转录病毒感染过程中的相互作用。我们的合作研究旨在提供功能、生化、细胞和分子水平的新的和集成的信息。我们的具体目标是：1.验证NO调节失调是可卡因心血管毒性的关键机制这一假说。-体内超声心动图和孤立的血管功能将与组织脂质过氧化、蛋白质硝化、一氧化氮合酶亚型和抗氧化酶有关。转基因小鼠将被使用。2.确定心脏对可卡因损伤的反应。-将评估组织对损伤的反应，包括免疫细胞渗透、形态和细胞凋亡。分离的肌细胞电生理学、收缩蛋白功能和肌球蛋白亚型的表达也将被检测。3.检验可卡因和小鼠艾滋病联合作用后心脏和血管功能障碍增强的假设。-将评估心血管功能、细胞、生化和分子参数。4.用人类尸检组织证实我们在老鼠身上的研究结果。-将检查艾滋病毒/艾滋病患者的心脏样本。这些研究将提供关于可卡因和逆转录病毒诱导的并发症机制的新信息，并提供关于免疫和心血管系统相互作用的重要见解。

The combination of cocaine abuse and HIV infection is an emerging problem and unique challenge for clinicians and researchers. Both are associated with cardiovascular complications alone, including acute events (angina, arrhythmias, myocardial infarction) and chronic conditions (myocarditis, vasculopathy, cardiomyopathy, congestive heart failure), but the mechanisms involved are undefined and and therapeutic strategies have not been optimized. Since they often coexist, it is reasonable to evaluate the pathophysiologic consequences of their combination. In this proposal our primary objectives are to define the mechanisms of cocaine induced cardiovascular dysfunction, and to determine the interactions of cocaine during retroviral infection, using an established and relevant animal model (murine AIDS, LPBM5 infection). Our collaborative studies are designed to provide new and integrated information at the functional, biochemical, cellular, and molecular levels. Our SPECIFIC AIMS are: 1. Test the hypothesis that dysregulation of NO is a key mechanism of cocaine-induced cardiovascular toxicity. -In vivo echocardiography and isolated vascular function will be related to tissue lipid peroxidation, protein nitration, NOS isoforms, and antioxidant enzymes. Transgenic mice will be employed. 2. Define cardiac responses to cocaine induced injury. -Tissue responses to injury will be evaluated, including immune cell infiltration, morphology, and apoptosis. Isolated myocyte electrophysiology, contractile protein function, and myosin isoform expression will also be examined. 3. Test the hypothesis that cardiac and vascular dysfunction is enhanced following cocaine and murine AIDS in combination. -Cardiovascular function, cellular, biochemical, and molecular parameters will be evaluated. 4. Corroborate the findings from our mouse studies using human autopsy tissues. -Cardiac specimens from HIV/AIDS patients will be examined. These studies will yield new information regarding mechanisms of cocaine- and retrovirus-induced complications and provide important insights regarding immune and cardiovascular system interactions.