ETHANOL & AIDS CARDIOMYOPATHY--MITOCHONDRIAL CONNECTION

已知慢性乙醇（EtOH）暴露和艾滋病暴露会导致心肌病，并且当结合时协同作用。此外，乙醇和艾滋病暴露都被观察到抑制线粒体功能，改变线粒体结构，并增加氧化应激。 线粒体氧化磷酸化的抑制减少线粒体能量产生并增加线粒体活性氧（ROS）产生，这分别与肥厚型心肌病和扩张型心肌病有关。 因此，我们假设乙醇和艾滋病暴露通过直接破坏OXPHOS和线粒体ROS间接抑制OXPHOS来减少线粒体能量产生，从而诱导心肌病。为了验证这一假设，我们建议挑战小鼠窝藏各种遗传缺陷的线粒体能量生产和ROS解毒慢性乙醇，小鼠艾滋病（MAIDS），乙醇加MAIDS暴露。 这四种品系将包括（1）野生型小鼠，（2）腺嘌呤核苷酸转运子（ANT 1）线粒体心肌亚型缺陷（-/-）小鼠，（3）线粒体Mn超氧化物歧化酶（MnSOD）部分缺陷（+/-）小鼠，和（4）谷胱甘肽过氧化物酶（GPx）缺陷（-/-）小鼠。 抗缺陷减少线粒体ATP对心脏的可用性，易患肥厚型心肌病。 MnSOD缺陷增加线粒体ROS产生并导致扩张型心肌病。GPx 1缺陷增加心脏细胞溶质过氧化氢水平，并增加病毒性心肌炎的可能性。然后分析对照、乙醇、MAIDS和乙醇+ MAIDS暴露的小鼠的心脏病理学、心脏线粒体OXPHOS的变化、增加的心脏氧化损伤以及线粒体和氧化应激基因表达的表达改变。 如果ANT -/-动物发展为更严重的肥厚型心肌病，并且在乙醇和MAIDS暴露下对扩张型心肌病的偏好增加，那么这将表明线粒体能量缺乏在心肌病中很重要。 如果MnSOD +/-动物具有增加的扩张型心肌病的频率，则这将涉及线粒体ROS毒性。 如果GPx 1-/-动物心肌炎的发病率增加，那么这将表明细胞溶质氧化应激在诱导的心肌病中很重要。

Chronic ethanol (EtOH) exposure and AIDS exposure are known to cause cardiomyopathy, and to act synergistically when combined. Moreover, both ethanol and AIDS exposure have been observed to inhibit mitochondrial function, alter mitochondrial structure, and increase oxidative stress. Inhibition of mitochondrial oxidative phosphorylation reduces mitochondrial energy production and increases mitochondrial reactive oxygen species (ROS) generation, which have been linked to hypertrophic cardiomyopathy and dilated cardiomyopathy, respectively. Therefore, we hypothesize that both ethanol and AIDS exposure induce cardiomyopathy by reducing mitochondrial energy production through the direct disruption of OXPHOS and the indirect inhibition of OXPHOS by mitochondrial ROS. To test this hypothesis, we propose to challenge mice harboring various genetic defects in mitochondrial energy production and ROS detoxification to chronic ethanol, murine AIDS (MAIDS), and ethanol plus MAIDS exposure. The four strains will include (1) wildtype mice, (2) mice deficient (-/-) in the mitochondrial heart-muscle isoform of the adenine nucleotide translocator (ANT1), (3) mice partially deficient (+/-) in the mitochondrial Mn superoxide dismutase (MnSOD), and (4) mice deficient (-/-)in the glutathione peroxidase (GPx). The ANTI-defect reduces mitochondrial ATP availability to the heart and predisposes to hypertrophic cardiomyopathy. The MnSOD-defect increases mitochondrial ROS production and leads to dilated cardiomyopathy. The GPx1 -defect increases cardiac cytosolic hydrogen peroxide levels and increases the potential for viral myocarditis. Control, ethanol, MAIDS, and ethanol + MAIDS exposed mice will then be analyzed for cardiac pathology, changes in cardiac mitochondrial OXPHOS, increased cardiac oxidative damage, and alterations in the expression of mitochondrial and oxidative stress gene expression. If the ANT -/- animals develop a more severe hypertrophic cardiomyopathy and an increased predilection to dilated cardiomyopathy an ethanol and MAIDS exposure then this will indicate that mitochondrial energy deficiency is important in cardiomyopathy. If the MnSOD +/- animals have an increased frequency of dilated cardiomyopathy, then this will implicate mitochondrial ROS toxicity. If the GPx1 -/- animals have an increased incidence of myocarditis, then this will indicate that cytosolic oxidative stress is important in induced cardiomyopathy.