Mitochondrial Dysfunction In Human Immunodeficiency Virus-1 Transgenic Mouse Cardiac Myocytes

The pathophysiology of human immunodeficiency virus (HIV)-associated cardiomyopathy remains uncertain. We used HIV-1 transgenic (Tg26) mice to explore mechanisms by which HIV-related proteins impacted on myocyte function. Compared to adult ventricular myocytes isolated from nontransgenic (wild type [WT]) littermates, Tg26 myocytes had similar mitochondrial membrane potential ((m)) under normoxic conditions but lower (m) after hypoxia/reoxygenation (H/R). In addition, (m) in Tg26 myocytes failed to recover after Ca2+ challenge. Functionally, mitochondrial Ca2+ uptake was severely impaired in Tg26 myocytes. Basal and maximal oxygen consumption rates (OCR) were lower in normoxic Tg26 myocytes, and further reduced after H/R. Complex I subunit and ATP levels were lower in Tg26 hearts. Post-H/R, mitochondrial superoxide (O-2(center dot-)) levels were higher in Tg26 compared to WT myocytes. Overexpression of B-cell lymphoma 2-associated athanogene 3 (BAG3) reduced O-2(center dot-) levels in hypoxic WT and Tg26 myocytes back to normal. Under normoxic conditions, single myocyte contraction dynamics were similar between WT and Tg26 myocytes. Post-H/R and in the presence of isoproterenol, myocyte contraction amplitudes were lower in Tg26 myocytes. BAG3 overexpression restored Tg26 myocyte contraction amplitudes to those measured in WT myocytes post-H/R. Coimmunoprecipitation experiments demonstrated physical association of BAG3 and the HIV protein Tat. We conclude: (a) Under basal conditions, mitochondrial Ca2+ uptake, OCR, and ATP levels were lower in Tg26 myocytes; (b) post-H/R, (m) was lower, mitochondrial O-2(center dot-) levels were higher, and contraction amplitudes were reduced in Tg26 myocytes; and (c) BAG3 overexpression decreased O-2(center dot-) levels and restored contraction amplitudes to normal in Tg26 myocytes post-H/R in the presence of isoproterenol.