HOPX Plays a Critical Role in Antiretroviral Drugs Induced Epigenetic Modification and Cardiac Hypertrophy.

Shiridhar Kashyap,Olena Kondrachuk,Mahnoush Sophia Shafiei,Raj Patel,Avni Mukker,Manish Kumar Gupta,Aishwarya Rajakumar,Isabela De Lima,Maryam Rabbani

doi:10.3390/cells10123458

Shiridhar Kashyap, Olena Kondrachuk + Show 7 more

Open Access

https://doi.org/10.3390/cells10123458

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Journal: Cells	Publication Date: Dec 8, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: University of Central Florida

Abstract

People living with HIV (PLWH) have to take an antiretroviral therapy (ART) for life and show noncommunicable illnesses such as chronic inflammation, immune activation, and multiorgan dysregulation. Recent studies suggest that long-term use of ART induces comorbid conditions and is one of the leading causes of heart failure in PLWH. However, the molecular mechanism of antiretroviral drugs (ARVs) induced heart failure is unclear. To determine the mechanism of ARVs induced cardiac dysfunction, we performed global transcriptomic profiling of ARVs treated neonatal rat ventricular cardiomyocytes in culture. Differentially expressed genes were identified by RNA-sequencing. Our data show that ARVs treatment causes upregulation of several biological functions associated with cardiotoxicity, hypertrophy, and heart failure. Global gene expression data were validated in cardiac tissue isolated from HIV patients having a history of ART. Interestingly, we found that homeodomain-only protein homeobox (HOPX) expression was significantly increased in cardiomyocytes treated with ARVs and in the heart tissue of HIV patients. Furthermore, we found that HOPX plays a crucial role in ARVs mediated cellular hypertrophy. Mechanistically, we found that HOPX plays a critical role in epigenetic regulation, through deacetylation of histone, while the HDAC inhibitor, Trichostatin A, can restore the acetylation level of histone 3 in the presence of ARVs.

Highlights

According to a recent study published by the World Health Organization, 37.7 million people are living with HIV infection globally, and almost 27.7 million people have access to antiretroviral drugs (ARVs) [1]
Through a loss-of-function and gain-in functional approach, we found that HOPX plays a critical role in the ARV-mediated epigenetic modification and induction of cardiomyocyte hypertrophy
These results indicate that ARV treatment modulates cellular function, through the regulation of genes associated with energy metabolism, cellular division, and cell death

Summary

Introduction

According to a recent study published by the World Health Organization, 37.7 million people are living with HIV infection globally, and almost 27.7 million people have access to antiretroviral drugs (ARVs) [1]. Due to the efficacy of antiretroviral therapy (ART), viral replication is inhibited, and the viral load becomes undetectable in the patients’ serum. People living with HIV (PLWH) have to commit to ARVs for the rest of their life to suppress viral reactivation [2,3]. Successful application of ART has significantly improved life expectancy in the PLWH and turned HIV from a terminal disease into a chronic disease. PLWH show an onset of non-HIV-related symptoms such as chronic inflammation, an unusual immune system, and a higher risk of cardiovascular disease (CVD) [4–6]. The relative risk of various CVDs in HIV patients has tripled since HIV was first reported, with a 61% increase in relative risk of CVDs, such as ischemic stroke, heart failure (HF), pulmonary hypertension, myocardial infarction, and venous thrombosis [7]

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