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

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.

Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials

“… 270 Trichostatin A and emodin have good clinical value in the treatment of cardiac hypertrophy and heart failure, through deacetylation of histone. 271 , 272 It was found that MPT0E014 generated beneficial impact in heart failure by inhibiting HDAC, increasing cardiac function, and alleviating the effects of heart failure on cardiometabolism and inflammation. 273 HDAC class I inhibitor Mocetinostat reverses myocardial fibrosis in heart failure by reducing myocardial fibroblast activation and inducing cell cycle arrest/apoptosis.…”

Direct and indirect cardiovascular and cardiometabolic sequelae of the combined anti-retroviral therapy on people living with HIV

“…The Hopx gene has been closely studied and found to be upregulated in cART-treated PLHIV and plays a key role with regards to cardiomyocyte hypertrophy. Kashyap et al (2021) ( Kashyap et al, 2021a ) has also shown in their studies with knockout mice that Hopx expression causes increased size in cardiomyocytes while knockout mice showed size reduction. Furthermore, the Hopx gene has been proposed to negatively impact proliferation and diferentiation of cardiomyocytes ( Chen et al, 2002 ).…”

“…The exact mechanisms by which cART leads to heart dysfunction and toxicity at the cellular level have not been elucidated. However, studies have been able to show that cART treatment leads to oxidative stress, cellular hypertrophy, and modified histones in cardiomyocytes ( Kashyap et al, 2021a ; Kashyap et al, 2021b ). In addition, RNA-seq data analysis has demonstrated that differences in gene expression causes changes at the transcriptional level ultimately causing cardiac hypertrophy and toxicity ( Kashyap et al, 2021a ).…”

“…However, studies have been able to show that cART treatment leads to oxidative stress, cellular hypertrophy, and modified histones in cardiomyocytes ( Kashyap et al, 2021a ; Kashyap et al, 2021b ). In addition, RNA-seq data analysis has demonstrated that differences in gene expression causes changes at the transcriptional level ultimately causing cardiac hypertrophy and toxicity ( Kashyap et al, 2021a ). In particular, they found through their studies of qRT-PCR of cART treated cardiomyocytes major genes associated with cardiac hypertrophy.…”

“…In particular, they found through their studies of qRT-PCR of cART treated cardiomyocytes major genes associated with cardiac hypertrophy. The main genes that were found to be elevated in these cells and cardiac tissue of PLHIV treated with cART were Hopx, P2rx4, and Ackr3 ( Kashyap et al, 2021a ). The Hopx gene has been closely studied and found to be upregulated in cART-treated PLHIV and plays a key role with regards to cardiomyocyte hypertrophy.…”