Mitochondrial Dysfunction in HIV-1 Transgenic Mouse Cardiac Myocytes
| Autor: | 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. |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Membrane Potential
Mitochondrial HIV Infections Mice Transgenic Myocardial Contraction Article Cell Hypoxia Mitochondria Heart Ventricular Function Left Mice Inbred C57BL Disease Models Animal Oxidative Stress Oxygen Consumption HIV-1 Animals Myocytes Cardiac Apoptosis Regulatory Proteins Cardiomyopathies Energy Metabolism Reactive Oxygen Species Oxidation-Reduction Cells Cultured Adaptor Proteins Signal Transducing Signal Transduction |
| Popis: | 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 non-transgenic (WT) littermates, Tg26 myocytes had similar mitochondrial membrane potential (Δ(m)) under normoxic conditions but lower ΔΨ(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 Bcl2-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. Co-immunoprecipitation experiments demonstrated physical association of BAG3 and the HIV protein Tat. We conclude: (i) under basal conditions, mitochondrial Ca(2+) uptake, OCR and ATP levels were lower in Tg26 myocytes; (ii) post-H/R, ΔΨ(m) was lower, mitochondrial O(2)(.−) levels were higher, and contraction amplitudes were reduced in Tg26 myocytes; (iii) BAG3 overexpression decreased O(2)(.−) levels and restored contraction amplitudes to normal in Tg26 myocytes post-H/R in the presence of isoproterenol. |
| Databáze: | OpenAIRE |
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