ETHANOL & AIDS CARDIOMYOPATHY--MITOCHONDRIAL CONNECTION

众所周知，长期接触乙醇(Etoh)和接触艾滋病会导致心肌病，当它们结合在一起时，会产生协同作用。此外，已经观察到酒精和艾滋病暴露都会抑制线粒体功能，改变线粒体结构，增加氧化应激。线粒体氧化磷酸化的抑制减少了线粒体能量的产生，增加了线粒体活性氧(ROS)的产生，它们分别与肥厚型心肌病和扩张型心肌病有关。因此，我们假设酒精和艾滋病暴露都通过直接破坏OXPHOS和通过线粒体ROS间接抑制OXPHOS而减少线粒体能量产生而导致心肌病。为了验证这一假设，我们建议挑战在线粒体能量产生和ROS解毒方面存在各种遗传缺陷的小鼠，以应对慢性乙醇、小鼠艾滋病(女仆)和乙醇加女仆的暴露。这四个品系将包括(1)野生型小鼠，(2)腺核苷酸转运子(ANT1)线粒体心肌-肌肉异构体缺陷(-/-)小鼠，(3)线粒体锰超氧化物歧化酶(MnSOD)部分缺乏(/-)小鼠，以及(4)谷胱甘肽过氧化物酶(-/-)缺乏小鼠。这种抗缺陷降低了线粒体ATP对心脏的可获得性，并易患肥厚性心肌病。MnSOD缺陷增加线粒体ROS的产生，导致扩张型心肌病。GPX1缺陷增加了心肌细胞内过氧化氢水平，增加了病毒性心肌炎的可能性。然后将分析对照组、乙醇、女佣和乙醇女仆暴露的小鼠的心脏病理、心肌线粒体OXPHOS的变化、心脏氧化损伤增加以及线粒体和氧化应激基因表达的变化。如果ANT-/-动物发展成更严重的肥厚性心肌病，增加了对扩张型心肌病、酒精和女仆暴露的偏好，那么这将表明线粒体能量缺乏在心肌病中是重要的。如果MnSOD/-动物扩张型心肌病的频率增加，那么这将意味着线粒体ROS毒性。如果GPX1-/-动物心肌炎的发病率增加，这将表明胞质氧化应激在诱导性心肌病中起重要作用。

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.