Alcohol Enhances HIV-1 Induced Cardiac Depression

酒精会增强 HIV-1 引起的心脏抑制

• 批准号: 6798691
• 负责人: KATHLEEN H MCDONOUGH
• 金额: $ 12.94万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6798691
• 关键词: HIV infections; antiAIDS agent; antioxidants; antiviral agents; cytokine; drug adverse effect; endotoxins; ethanol; gene environment interaction; gene expression; genetically modified animals; heart contraction; heart function; human immunodeficiency virus 1; laboratory mouse; myocardium; myocardium disorder; oxidative stress; physiologic stressor; toxicology; transcription factor; virus genetics; virus protein; zidovudine

DESCRIPTION (provided by applicant): The expression of the HIV protein, Tat, has global effects on cell function including alterations in cytokine expression, transcription factors, and oxidative state of the cells. Most of these are important modulators of myocardial function and may exert potent effects particularly when the heart is stressed. The ability of the heart to respond to the increased demands requires use of metabolic reserve to supply high energy phosphates, and contractile reserve elicited by mobilizing calcium supplies for greater contractility and heart rate. In utilizing these reserves, mitochondrial function is enhanced, as is leakage of oxygen radicals. Loss of antioxidant capacity may compromise myocardial function during increased work and increased metabolic demand and especially during oxidative stress and increased cytokine production subsequent to endotoxin administration. The hypotheses to be tested in this proposal are three fold: 1) HIV-1 infection, as studied with a transgenic mouse model in which the Tat gene promoter is expressed and Tat protein is present in many tissues, causes loss of myocardial contractile reserve, i.e. impairs the response of the heart to physiologic stresses and leaves the heart more susceptible to injury from oxidative challenge and endotoxemia; 2) chronic alcohol consumption potentiates the detrimental effects of HIV (Tat expression) on myocardial function and reserve; and 3) treatment with the antiretroviral agent, AZT, potentiates the effects of Tat and alcohol on myocardial function and reserve. Alcohol and AZT treatment exacerbate Tat induced dysfunction by further upsetting the antioxidant balance in cells and promoting cytokine production. The function of the heart will be assessed with the isolated work performing heart and plasma and tissue cytokines and biochemical markers of myocardial oxidative injury and antioxidant capacity will be measured by standard techniques.

描述（由申请人提供）： HIV 蛋白 Tat 的表达对细胞功能具有整体影响，包括改变 细胞因子表达、转录因子和细胞的氧化状态。其中大部分是 心肌功能的重要调节剂，可能发挥有效作用，特别是当 心里有压力。心脏对增加的需求做出反应的能力需要使用 提供高能磷酸盐的代谢储备，以及通过调动钙供应以提高收缩力和心率而引起的收缩储备。在利用这些储备的过程中，线粒体功能得到增强，氧自由基的泄漏也得到增强。抗氧化能力的丧失可能会在工作量增加和代谢需求增加期间损害心肌功能，特别是在氧化应激和内毒素施用后细胞因子产生增加期间。该提案中要测试的假设有三个方面：1) HIV-1 感染，如用转基因小鼠模型所研究的，其中 Tat 基因启动子表达且 Tat 蛋白存在于许多组织中，导致心肌收缩储备丧失，即损害心脏对生理应激的反应，并使心脏更容易受到氧化挑战和内毒素血症的伤害； 2) 长期饮酒会加剧 HIV（Tat 表达）对心肌功能和储备的不利影响； 3) 抗逆转录病毒药物 AZT 治疗可增强 Tat 和酒精对心肌功能和储备的影响。酒精和 AZT 治疗会进一步扰乱细胞中的抗氧化平衡并促进细胞因子的产生，从而加剧 Tat 诱导的功能障碍。将通过执行心脏和血浆和组织细胞因子的孤立工作来评估心脏功能，并通过标准技术测量心肌氧化损伤和抗氧化能力的生化标志物。