Mitochondrial dysfunction in human immunodeficiency virus-1 transgenic mouse cardiac myocytes.

Journal Article

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 (ΔΨ m ) under normoxic conditions but lower Δ Ψ m after hypoxia/reoxygenation (H/R). In addition, Δ Ψ 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, Δ Ψ 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.

Full Text

Duke Authors

Cited Authors

  • Cheung, JY; Gordon, J; Wang, J; Song, J; Zhang, X-Q; 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

Published Date

  • April 2019

Published In

Volume / Issue

  • 234 / 4

Start / End Page

  • 4432 - 4444

PubMed ID

  • 30256393

Pubmed Central ID

  • 30256393

Electronic International Standard Serial Number (EISSN)

  • 1097-4652

Digital Object Identifier (DOI)

  • 10.1002/jcp.27232

Language

  • eng

Conference Location

  • United States