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

Joseph Y. Cheung, Jennifer Gordon, Ju Fang Wang, Jianliang Song, Xue Qian Zhang, Fabian Jana Prado, Santhanam Shanmughapriya, Sudarsan Rajan, Dhanendra Tomar, Farzaneh G. Tahrir, Manish K. Gupta, Tijana Knezevic, Nana Merabova, Christopher D. Kontos, Joseph M. McClung, Paul E. Klotman, Madesh Muniswamy, Kamel Khalili, Arthur M. Feldman

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalJournal of Cellular Physiology
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

Viruses
Cardiac Myocytes
Muscle Cells
Transgenic Mice
HIV-1
Isoproterenol
Adenosine Triphosphate
Oxygen
Human Immunodeficiency Virus Proteins
Superoxides
Cells
Membranes
Oxygen Consumption
Proteins
Experiments
Mitochondrial Membrane Potential
B-Cell Lymphoma
Cardiomyopathies

Keywords

  • adenovirus
  • adult myocyte culture
  • HIV cardiomyopathy
  • mitochondria bioenergetics
  • reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Cheung, J. Y., Gordon, J., Wang, J. F., Song, J., Zhang, X. Q., Prado, F. J., ... Feldman, A. M. (Accepted/In press). Mitochondrial dysfunction in human immunodeficiency virus-1 transgenic mouse cardiac myocytes. Journal of Cellular Physiology. https://doi.org/10.1002/jcp.27232

Mitochondrial dysfunction in human immunodeficiency virus-1 transgenic mouse cardiac myocytes. / Cheung, Joseph Y.; Gordon, Jennifer; Wang, Ju Fang; Song, Jianliang; Zhang, Xue Qian; Prado, Fabian Jana; Shanmughapriya, Santhanam; Rajan, Sudarsan; Tomar, Dhanendra; Tahrir, Farzaneh G.; Gupta, Manish K.; Knezevic, Tijana; Merabova, Nana; Kontos, Christopher D.; McClung, Joseph M.; Klotman, Paul E.; Muniswamy, Madesh; Khalili, Kamel; Feldman, Arthur M.

In: Journal of Cellular Physiology, 01.01.2018.

Research output: Contribution to journalArticle

Cheung, JY, Gordon, J, Wang, JF, 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, Muniswamy, M, Khalili, K & Feldman, AM 2018, 'Mitochondrial dysfunction in human immunodeficiency virus-1 transgenic mouse cardiac myocytes', Journal of Cellular Physiology. https://doi.org/10.1002/jcp.27232
Cheung, Joseph Y. ; Gordon, Jennifer ; Wang, Ju Fang ; Song, Jianliang ; Zhang, Xue Qian ; Prado, Fabian Jana ; Shanmughapriya, Santhanam ; Rajan, Sudarsan ; Tomar, Dhanendra ; Tahrir, Farzaneh G. ; Gupta, Manish K. ; Knezevic, Tijana ; Merabova, Nana ; Kontos, Christopher D. ; McClung, Joseph M. ; Klotman, Paul E. ; Muniswamy, Madesh ; Khalili, Kamel ; Feldman, Arthur M. / Mitochondrial dysfunction in human immunodeficiency virus-1 transgenic mouse cardiac myocytes. In: Journal of Cellular Physiology. 2018.
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AU - Gordon, Jennifer

AU - Wang, Ju Fang

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AU - Zhang, Xue Qian

AU - Prado, Fabian Jana

AU - Shanmughapriya, Santhanam

AU - Rajan, Sudarsan

AU - Tomar, Dhanendra

AU - Tahrir, Farzaneh G.

AU - Gupta, Manish K.

AU - Knezevic, Tijana

AU - Merabova, Nana

AU - Kontos, Christopher D.

AU - McClung, Joseph M.

AU - Klotman, Paul E.

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AU - Khalili, Kamel

AU - Feldman, Arthur M.

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