While long term combined antiretroviral therapy (cART) has greatly improved survival rates among AIDS patients, a substantial proportion of HIV-1 infected individuals continue to develop comorbidities including heart failure (HF) secondary to left ventricular dysfunction at higher rates than non-HIV-1 individuals. The underlying mechanisms whereby HIV-1 increases susceptibility to HF remain poorly understood. In this respect, HIV-1 Tat, which is produced and released by the latent viral reservoir and upon its circulation can be taken up by uninfected cells, has received special attention due to its ability to induce an array of dysregulatory events that perturb cell and organ function. HIV-1 Tat has the capacity to induce injury and promote death in a broad range of cells including myocytes, and its expression promotes cardiac disease in laboratory animals. Our recent studies demonstrate that HIV-1 Tat physically associates with BAG3, a stress induced protein which is involved in protein quality control, and modulates autophagy and apoptosis. BAG3 is critical for normal cardiac development and maintenance as BAG3 knockout mice develop left ventricular (LV) dysfunction and have a shortened lifespan. Furthermore, recent studies have identified a potential role for BAG3 in patients with HF as heterozygous mutations that decrease the level of BAG3 have been identified in patients with HF within families who develop a heritable form of dilated cardiomyopathy. Moreover, ventricular myocardium isolated from failing human hearts examined at the time of heart transplantation exhibit nearly 50% reduction in BAG3 levels in cardiac tissue, all of which supports the importance of BAG3 for healthy heart function. At the subcellular level, the association of BAG3 with the actin capping protein, CapZ?1, promotes its complexation with Hsp70, events that stabilize CapZ?1and facilitate its proper subcellular distribution in cardiomyocytes. In addition, BAG3 is an important regulator of filamin and myopodin and regulates protein turnover by autophagy in cardiomyocytes. Our preliminary results suggest that the interplay between BAG3 and HIV-1 Tat impacts the ability of BAG3 to regulate several pathways involved in the structural and functional integrity of cardiomyocytes. Thus, one can envision a model in which the inactivation of BAG3, upon its association with HIV-1 Tat, recapitulates the clinical manifestations seen in patients with heart failure associated with low/dysfunctional BAG3. By capitalizing on the expertise of two groups of accomplished investigators in cardiovascular research and in HIV-1 pathogenesis and BAG3 biology, we will investigate the cellular and molecular mechanisms involved in HIV-1 induced cardiomyopathy in cell cultures, animal models, and clinical samples. The outcome of these studies will provide a unique set of information aimed at developing prognostic biomarkers of disease severity and therapeutic strategies for treating HIV-1 associated cardiomyopathy.
Long term antiretroviral therapy for HIV-1/AIDS has resulted in increased survival, but individuals living longer with HIV-1 develop comorbidities at much higher rates than uninfected individuals, and are especially vulnerable to diseases of aging such as heart disease. HIV-1 infection affects the ability of heart muscle cells to function properly an understanding the mechanisms related to how HIV-1 damages the heart can lead to the development of prognostic markers and more targeted therapeutic strategies to protect the heart and reduce the incidence of cardiomyopathy in HIV-1 infected patients.
|Bao, Lei; Chen, Shu-Jen; Conrad, Kathleen et al. (2016) Depletion of the Human Ion Channel TRPM2 in Neuroblastoma Demonstrates Its Key Role in Cell Survival through Modulation of Mitochondrial Reactive Oxygen Species and Bioenergetics. J Biol Chem 291:24449-24464|
|Feldman, Arthur M; Gordon, Jennifer; Wang, JuFang et al. (2016) BAG3 regulates contractility and Ca(2+) homeostasis in adult mouse ventricular myocytes. J Mol Cell Cardiol 92:10-20|
|Gupta, Manish K; Tahrir, Farzaneh G; Knezevic, Tijana et al. (2016) GRP78 Interacting Partner Bag5 Responds to ER Stress and Protects Cardiomyocytes From ER Stress-Induced Apoptosis. J Cell Biochem 117:1813-21|
|Hoffman, Nicholas E; Miller, Barbara A; Wang, JuFang et al. (2015) CaÂ²âº entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance. Am J Physiol Heart Circ Physiol 308:H637-50|
|Cheung, Joseph Y; Gordon, Jennifer; Wang, JuFang et al. (2015) Cardiac Dysfunction in HIV-1 Transgenic Mouse: Role of Stress and BAG3. Clin Transl Sci 8:305-10|
|Knezevic, Tijana; Myers, Valerie D; Gordon, Jennifer et al. (2015) BAG3: a new player in the heart failure paradigm. Heart Fail Rev 20:423-34|
|Feldman, Arthur M; Begay, Rene L; Knezevic, Tijana et al. (2014) Decreased levels of BAG3 in a family with a rare variant and in idiopathic dilated cardiomyopathy. J Cell Physiol 229:1697-702|
|White, Martyn K; Kaminski, Rafal; Khalili, Kamel et al. (2014) Rad51 activates polyomavirus JC early transcription. PLoS One 9:e110122|
|Bruno, Anna Paola; De Simone, Francesca Isabella; Iorio, Vittoria et al. (2014) HIV-1 Tat protein induces glial cell autophagy through enhancement of BAG3 protein levels. Cell Cycle 13:3640-4|