Targeting epigenetic mechanisms as an emerging therapeutic strategy in pulmonary hypertension disease

Abstract

Pulmonary arterial hypertension (PAH) is a multifactorial cardiopulmonary disease characterized by an elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), which can lead to right ventricular (RV) failure, multi-organ dysfunction, and ultimately to premature death. Despite the advances in molecular biology, the mechanisms underlying pulmonary hypertension (PH) remain unclear. Nowadays, there is no curative treatment for treating PH. Therefore, it is crucial to identify novel, specific therapeutic targets and to offer more effective treatments against the progression of PH. Increasing amounts of evidence suggest that epigenetic modification may play a critical role in the pathogenesis of PAH. In the presented paper, we provide an overview of the epigenetic mechanisms specifically, DNA methylation, histone acetylation, histone methylation, and ncRNAs. As the recent identification of new pharmacological drugs targeting these epigenetic mechanisms has opened new therapeutic avenues, we also discuss the importance of epigenetic-based therapies in the context of PH.

Keywords: PAH; epigenetics; vascular remodelling.

Figure 1

Pathogenesis of pulmonary hypertension. PAH is associated with vascular and cardiac remodeling. In PAH, vascular remodeling is characterized by smooth muscle and endothelial cell dysfunction. Indeed, both cell types contribute to muscularization, obstruction, and constriction of distal pulmonary arteries (PAs) which progressively increase the vascular resistance to induce right ventricle (RV) hypertrophy and ultimately RV dysfunction. Representative pictures of the vascular remodeling in pulmonary arterioles have been previously published by Dr Hadri and collaborators (185). PAH, pulmonary arterial hypertension; PASMC, pulmonary artery smooth muscle cells; PAEC, pulmonary artery endothelial cell.

Figure 2

Updated classification of pulmonary hypertension. The World Health Organization classifies PH into five groups based on the underlying etiology. Group I includes PAH. Group II refers to PH from left sided heart disease. Group III refers to PH caused by chronic hypoxia lung disease. Group IV is associated with chronic blood clots, and Group V includes all other forms of PH associated with unclear multifactorial mechanisms such as sarcoidosis and hematological disorders.

Figure 3

Major epigenetic mechanisms. There are three major layers of epigenetic modifications: DNA methylation, histone modifications, and non-coding RNAs. These epigenetic marks regulate the expression of genes. DNA methylation is regulated by enzymes called DNA methyltransferases and DNA demethyltransferases. Histone post-translational modifications occur on the N-terminal tails of four core histones (H3, H4, H2A, and H2B). Among the histone modifications, acetylation and methylation remain the most studied mechanisms. ncRNAs also play a critical role in gene expression by degrading their target mRNAs and/or inhibiting their translation. ncRNAs include miRNA, siRNA, Piwi-interacting RNA (piRNA), and lncRNA.

Figure 4

Illustration of several underlying epigenetic mechanisms in pulmonary hypertension. DNA methylation plays an important role in the regulation of the expression of superoxide dismutase 2 (SOD2) and bone morphogenetic protein receptor 2 (BMPR2). Low SOD2 and BMPR2 expression is associated with increased proliferation and decreased apoptosis in hPASMC. Several histone deacetylases (HDAC1, 4, 5, and 6) are upregulated in PAH. HDACs inhibitors (VPA, SAHA, MGCD0103, MS-275, and Vorinostat) have been extensively investigated in multiple experimental models of PH. miRNAs (i.e miR-17/29; -21; 20a; -135a; miR-124; mR-204) target key signaling pathways (i.e BMPR2 and PPARγ) to influence the proliferation and migration of PASMCs and PAECs. The aforementioned miRNAs regulate several processes such as BMPR2 and PPARγ and hypoxia and other pro-proliferative signaling pathways implicated in the development of PAH.