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Published on: September 20, 2018
Antiretroviral Drugs Regulate Epigenetic Modification of Cardiac Cells Through Modulation of H3K9 and H3K27
Shiridhar Kashyap1, Avni Mukker1, Deepti Gupta1
1Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States.
Insights
Antiretroviral drugs used for HIV treatment alter cardiac cell epigenetics, increasing cardiovascular disease risk. SIRT1 may protect heart cells from these drug-induced changes.
Area of Science:
- Cardiovascular Science
- Epigenetics
- HIV/AIDS Research
Background:
- Antiretroviral therapy (ART) improves HIV survival but increases cardiovascular disease (CVD) risk in people living with HIV (PLWH).
- The specific impact of antiretroviral (ARV) drugs on cardiac cells remains unclear.
Purpose of the Study:
- To investigate the effects of ARV drugs on cardiomyocyte epigenetic remodeling.
- To identify potential mechanisms linking ARV treatment to CVD in PLWH.
Main Methods:
- Primary cardiomyocytes were exposed to a combination of four ARV drugs.
- Epigenetic changes, including histone modifications (acetylation and methylation), reactive oxygen species (ROS) production, and cellular hypertrophy were assessed.
- Expression of chromatin remodeling enzymes (SIRT1, SUV39H1, EZH2) was analyzed via PCR array and protein levels.
- Gene expression in heart tissue from HIV+ patients with ART history was examined.
Main Results:
- ARV drug treatment reduced H3K9 and H3K27 acetylation while increasing methylation.
- ARV drugs elevated ROS production and induced cellular hypertrophy in cardiomyocytes.
- Expression of SIRT1, SUV39H1, and EZH2 was upregulated in ARV-treated cardiomyocytes and in HIV+ patients on ART.
- SIRT1 expression was found to protect cardiomyocytes by reducing ROS and hypertrophy.
Conclusions:
- ARV drugs induce epigenetic alterations in cardiomyocytes, specifically modulating histone marks associated with gene expression.
- These epigenetic changes contribute to cellular stress, ROS production, and hypertrophy, potentially explaining increased CVD risk in PLWH on ART.
- SIRT1 emerges as a protective factor against ARV-induced cardiac damage, suggesting potential therapeutic targets for CVD in this population.
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.
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