AIDS and Alcohol and Cardiomyopathy

描述（由申请人提供）：该项目定义了酒精，艾滋病， 和核苷类似物逆转录酶抑制剂（NRTI）治疗 导致线粒体能量消耗、氧化应激（失衡 自由基的产生和抗氧化防御之间），以及 心肌病（收缩衰竭; CM）。CM是一种常见且严重的 酒精使用的后果。其假定的机制包括氧化应激 改变了线粒体能量NRTI齐多夫定（AZT）是一种 艾滋病治疗的基石AZT通过能量机制在体内引起CM 耗尽AZT三磷酸盐抑制心肌线粒体DNA pol-gamma和 改变mtDNA复制。最近，AZT引起线粒体DNA氧化， 心脏线粒体结构，表明机械的重要性， 氧化应激由于NRTI治疗艾滋病和饮酒可能 在同一个病人中共存，（特别是随着艾滋病生存率的增加）， 合理假设加性或协同能量消耗或氧化 每个人的压力。工作假设指出：CM是由艾滋病、AZT和 酒精的使用。当艾滋病，AZT（或相关的NRTI治疗）和酒精 共同消耗发生，叠加或协同损害心脏 线粒体结果。线粒体损伤的机制包括能量 消耗和氧化应激。目的1：定义线粒体 能量消耗和氧化的生物发生和线粒体能量学 艾滋病、NRTI治疗和饮酒中的压力。mtDNA和mtDNA 丰富，线粒体多肽合成反映线粒体 生物起源和功能。总DNA和mtDNA中的氧化鸟苷（8-OhdG），以及 心肌谷胱甘肽（GSH/GSSG）含量是线粒体氧化损伤的标志物， 应力线粒体顺乌头酸酶失活反映了氧化损伤， 线粒体蛋白目的2：定义心脏功能改变 线粒体能量学和氧化应激从艾滋病，NRTI治疗， 酒精消费。连续超声心动图确定LV质量，壁厚， 以及腔室尺寸和缩短。分离的心脏被用来分析 在缺乏心室血管的情况下的心脏收缩性和舒张性 耦合和循环神经激素。目的3：定义心脏结构 这些特征是由改变的线粒体能量学和氧化 应力分析肌原纤维、细胞核和线粒体体积 定量（通过透射电子显微镜[TEM]）。体积分数 细胞外基质和肌细胞的细胞外基质通过形态测定法（光和 TEM）。

DESCRIPTION (provided by applicant): This project defines how alcohol, AIDS, and nucleoside analog reverse transcriptase inhibitor (NRTI) treatment contribute to mitochondrial energy depletion, oxidative stress (imbalance between production of free radicals and antioxidant defenses), and cardiomyopathy (contractile failure; CM). CM is a frequent and serious consequence of alcohol use. Its putative mechanisms include oxidative stress and altered mitochondrial energetics. The NRTI zidovudine (AZT) is a cornerstone of AIDS therapy. AZT causes CM in vivo through mechanisms of energy depletion. AZT triphosphate inhibits cardiac mitochondrial DNA pol-gamma and alters mtDNA replication. Recently, AZT caused oxidation of mtDNA and altered cardiac mitochondrial structure, suggesting the mechanistic importance of oxidative stress. Since NRTI treatment for AIDS and alcohol consumption may coexist in the same patient, (particularly as AIDS survival increases), it is reasonable to hypothesize additive or synergistic energy depletion or oxidative stress from each. The working hypothesis states: CM results from AIDS, AZT, and from alcohol use. When AIDS, AZT (or related NRTI therapy), and alcohol consumption occur together, additive or synergistic damage to cardiac mitochondria results. Mechanisms for mitochondrial damage include energy depletion and oxidative stress. The AIMS are: AIM 1: to define mitochondrial biogenesis and mitochondrial energetics in energy depletion and oxidative stress in AIDS, NRTI therapy and alcohol consumption. mtDNA and mtRNA abundance, and mitochondrial polypeptide synthesis reflect mitochondrial biogenesis and function. Oxidized guanosine (8-OhdG) in total- and mtDNA, and cardiac glutathione (GSH/GSSG) content are markers of mitochondrial oxidative stress. Mitochondrial aconitase inactivation reflects oxidative damage to mitochondrial proteins. AIM 2: to define cardiac performance with altered mitochondrial energetics and oxidative stress from AIDS, NRTI therapy and alcohol consumption. Serial echocardiograms determine LV mass, wall thickness, and chamber dimensions and shortening. Isolated hearts are used to analyze cardiac contractility and relaxation in the absence of ventriculo-vascular coupling and circulating neurohormones. AIM 3: to define cardiac structural features that result from altered mitochondrial energetics and oxidative stress. Myofibrillar, nuclear and mitochondrial volumes are analyzed quantitatively (by transmission electron microscopy [TEM]). Volume fractions of extracellular matrix and of myocytes are determined morphometrically (light and TEM).