Mitochondrial dysfunction in human immunodeficiency virus‐1 transgenic mouse cardiac myocytes. Issue 4 (7th September 2018)

• Record Type: Journal Article
• Authors: Cheung, Joseph Y.; Gordon, Jennifer; Wang, JuFang; 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.; Madesh, Muniswamy; Khalili, Kamel; Feldman, Arthur M.
• Is Part Of: Journal of cellular physiology. Volume 234:Issue 4(2019:Apr.)
• Page Start: 4432
• Page End: 4444
• Publication Date: 2018-09-07
• Subjects: adenovirus -- adult myocyte culture -- HIV cardiomyopathy -- mitochondria bioenergetics -- reactive oxygen species; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.27232
• Languages: English
• ISSNs: 0021-9541

Abstract

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 (Δ Ψ 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. Abstract : The hemizygous NL4‐3 Δgag/pol transgenic (Tg26) mouse with replication‐deficient, noninfectious human immunodeficiency virus type 1 (HIV‐1) but with HIV‐1 proteins present in tissues simulates contemporary HIV‐1‐infected patients treated with combination antiretroviral therapy and is an excellent model to study chronic complications of HIV‐1 infection such as HIV‐associated cardiomyopathy. Cardiac myocytes isolated from Tg26 mice demonstrate mitochondrial dysfunction and elevated reactive oxygen species (ROS) that are exacerbated by hypoxia/reoxygenation and adrenergic stress. B‐cell lymphoma 2‐associated athanogene 3 (BAG3) regulates autophagy, apoptosis, excitation‐contraction coupling, mitochondrial quality control, and sarcomere stability in cardiac myocytes and can associate with the HIV‐1 protein Tat. Overexpression of BAG3 in Tg26 myocytes restores the elevated ROS levels to normal and improves contractile dysfunction. BAG3 may be a useful therapeutic modality in the treatment of HIV‐associated cardiomyopathy.