COCAINE AND CARDIOVASCULAR DYSFUNCTION IN MURINE AIDS

可卡因滥用和艾滋病毒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挑战。两者都单独与心血管并发症相关，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、血管病变、心肌病、充血性心力衰竭），但涉及的机制尚不明确，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。在这一提议中，我们的主要目标是确定可卡因诱导心血管功能障碍的机制，并确定可卡因在逆转录病毒感染期间的相互作用，使用已建立的相关动物模型（小鼠艾滋病，LPBM5感染）。我们的合作研究旨在在功能、生化、细胞和分子水平上提供新的和综合的信息。我们的具体目标是：1。验证NO的失调是可卡因引起心血管毒性的关键机制的假设。体内超声心动图和离体血管功能与组织脂质过氧化、蛋白质硝化、NOS异构体和抗氧化酶有关。将使用转基因小鼠。2. 定义心脏对可卡因损伤的反应。-评估组织对损伤的反应，包括免疫细胞浸润、形态学和凋亡。分离的肌细胞电生理、收缩蛋白功能和肌球蛋白异构体表达也将被检查。3. 验证可卡因和小鼠艾滋病联合使用后心脏和血管功能障碍增强的假设。-心血管功能、细胞、生化和分子参数将被评估。4. 用人体解剖组织证实我们小鼠研究的发现。-检查爱滋病患者的心脏样本。这些研究将产生有关可卡因和逆转录病毒诱导的并发症机制的新信息，并提供有关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.