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Cheung JY, Gordon J, Wang J, Song J, Zhang XQ, Prado FJ, Shanmughapriya S, Rajan S, Tomar D, Tahrir FG, Gupta MK, Knezevic T, Merabova N, Kontos CD, McClung JM, Klotman PE, Madesh M, Khalili K, Feldman AM
Mitochondrial dysfunction in human immunodeficiency virus-1 transgenic mouse cardiac myocytes
J Cell Physiol (2019) 234:4432-4444.
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 (DeltaPsi m) under normoxic conditions but lower Delta Psi m after hypoxia/reoxygenation (H/R). In addition, Delta Psi m in Tg26 myocytes failed to recover after Ca (2+) challenge. Functionally, mitochondrial Ca (2+) 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 (*-)) levels were higher in Tg26 compared to WT myocytes. Overexpression of B-cell lymphoma 2-associated athanogene 3 (BAG3) reduced O 2 (*-) 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 Ca (2+) uptake, OCR, and ATP levels were lower in Tg26 myocytes; (b) post-H/R, Delta Psi m was lower, mitochondrial O 2 (*-) levels were higher, and contraction amplitudes were reduced in Tg26 myocytes; and (c) BAG3 overexpression decreased O 2 (*-) levels and restored contraction amplitudes to normal in Tg26 myocytes post-H/R in the presence of isoproterenol.
Publication Date: 2019-04-01.
PMCID: PMC6318060
Last updated on Saturday, August 22, 2020