Abstract
Antiretroviral therapy (ART) has significantly reduced the rate of mortality in HIV infected population, but people living with HIV (PLWH) show higher rates of cardiovascular disease (CVD). However, the effect of antiretroviral (ARV) drug treatment on cardiac cells is not clear. In this study, we explored the effect of ARV drugs in cardiomyocyte epigenetic remodeling. Primary cardiomyocytes were treated with a combination of four ARV drugs (ritonavir, abacavir, atazanavir, and lamivudine), and epigenetic changes were examined. Our data suggest that ARV drugs treatment significantly reduces acetylation at H3K9 and H3K27 and promotes methylation at H3K9 and H3K27, which are histone marks for gene expression activation and gene repression, respectively. Besides, ARV drugs treatment causes pathological changes in the cell through increased production of reactive oxygen species (ROS) and cellular hypertrophy. Further, the expression of chromatin remodeling enzymes was monitored in cardiomyocytes treated with ARV drugs using PCR array. The PCR array data indicated that the expression of epigenetic enzymes was differentially regulated in the ARV drugs treated cardiomyocytes. Consistent with the PCR array result, SIRT1, SUV39H1, and EZH2 protein expression was significantly upregulated in ARV drugs treated cardiomyocytes. Furthermore, gene expression analysis of the heart tissue from HIV+ patients showed that the expression of SIRT1, SUV39H1, and EZH2 was up-regulated in patients with a history of ART. Additionally, we found that expression of SIRT1 can protect cardiomyocytes in presence of ARV drugs through reduction of cellular ROS and cellular hypertrophy. Our results reveal that ARV drugs modulate the epigenetic histone markers involved in gene expression, and play a critical role in histone deacetylation at H3K9 and H3K27 during cellular stress. This study may lead to development of novel therapeutic strategies for the treatment of CVD in PLWH.
Highlights
Human immunodeficiency virus (HIV) has infected 38 million people globally, and 1.7 million new cases were diagnosed in 2019 [1]
Western blot analysis showed that the protease inhibitors and reverse transcriptase inhibitor lamivudine had a greater deacetylation effect compared to the reverse transcriptase inhibitor abacavir (Figures 1G,H) These results suggest that ARV drugs modulate Post translational modifications (PTMs) of histone and cause significant reduction of active histone marks
Earlier studies reported that mono, di, and trimethylation of histone plays a significant role in the regulation of chromatin mediated gene expression in heart [29, 31, 32]
Summary
Human immunodeficiency virus (HIV) has infected 38 million people globally, and 1.7 million new cases were diagnosed in 2019 [1]. ART improves the life expectancy of people living with HIV (PLWH), it is known to increase the risk for developing cardiovascular disease (CVD) [2,3,4,5]. Patients receive a combination of two or three drugs, such as nucleoside reverse transcriptase inhibitors (lamivudine and abacavir), along with protease inhibitors (ritonavir and atazanavir) [18]. In 2020 international antiviral society- USA panel suggest that regimens of three drugs including 2 nucleoside reverse transcriptase inhibitor and an integrase inhibitor can be useful to suppress the viral replication [19], some of the developing nations continuously using the old regime of first line NRTIbased cocktail along with protease inhibitors [20,21,22]. Concordant with the clinical data, it was reported that combined ART causes cardiomyopathy and metabolic disorders in HIV mouse models [25]
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