Alcohol Enhances HIV-1 Induced Cardiac Depression

酒精会增强 HIV-1 引起的心脏抑制

基本信息

批准号：
7290701
负责人：
KATHLEEN H MCDONOUGH
金额：
$ 9.52万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
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

项目摘要

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全球影响，包括改变细胞因子表达，转录因子和细胞的氧化态。其中大多数是心肌功能的重要调节剂，并可能发挥有效的效果心脏压力很大。心脏对增加需求的响应的能力需要使用代谢储备可提供高能磷酸盐，并通过动员钙供应提高收缩性和心率而引起的收缩储备。在利用这些储量时，线粒体功能得到增强，氧自由基的泄漏也是如此。抗氧化能力的丧失可能会损害增加工作期间的心肌功能，并增加代谢需求，尤其是在氧化应激期间，并在内毒素给药后增加的细胞因子产生增加。该提案中要测试的假设是三个方面：1）HIV-1感染，如通过转基因小鼠模型所研究的，其中表达Tat基因启动子，并且在许多组织中都存在TAT蛋白，导致心肌储备的丧失，即心脏对心脏的反应损害，使心脏的反应更加损害，从而使心脏受到更加稳定的氧化和氧化运动的伤害，并且会损害氧化的氧化和氧化运动。 2）长期饮酒增强了HIV（TAT表达）对心肌功能和储备的有害影响； 3）用抗逆转录病毒剂AZT治疗，增强了TAT和酒精对心肌功能和储备的影响。酒精和AZT治疗通过进一步破坏细胞中的抗氧化剂平衡并促进细胞因子的产生，加剧了tat诱导功能障碍。心脏的功能将通过孤立的工作进行心脏和血浆，组织细胞因子以及心肌氧化损伤的生化标记和抗氧化能力的生化标记进行评估。