Insights on the epigenetic mechanisms underlying pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH), characterized by localized increased arterial blood pressure in the lungs, is a slow developing long-term disease that can be fatal. PAH is characterized by inflammation, vascular tone imbalance, pathological pulmonary vascular remodeling, and right-sided heart failure. Current treatments for PAH are palliative and development of new therapies is necessary. Recent and relevant studies have demonstrated that epigenetic processes may exert key influences on the pathogenesis of PAH and may be promising therapeutic targets in the prevention and/or cure of this condition. The aim of the present mini-review is to summarize the occurrence of epigenetic-based mechanisms in the context of PAH physiopathology, focusing on the roles of DNA methylation, histone post-translational modifications and non-coding RNAs. We also discuss the potential of epigenetic-based therapies for PAH.

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

“…In this review, we focused on different epigenetic mechanisms and emphasized on how they affect various cellular processes. Over the past years, it has become increasingly recognized that epigenetics may play a critical role in the initiation and progression of PAH, as demonstrated by the increasing amount of reviews recently published in the field (32,33,34). Here we present the most comprehensive and up-to-date review on the role of epigenetic mechanisms in the context of PAH.…”

Histone methylation and vascular biology

“…Thus, a better understanding of PAH pathogenesis contributes to the identification of new targets for therapy. The pathological features of PAH include augmented vasoconstriction, vascular obstruction, vascular stiffening, endothelial dysfunction, inflammation, fibrosis, and right ventricular failure [88,89]. Mechanisms that drive pathological vascular remodeling in the lungs of patients with PAH include cellular, genetic, and epigenetic changes.…”

“…Mechanisms that drive pathological vascular remodeling in the lungs of patients with PAH include cellular, genetic, and epigenetic changes. Published studies have largely focused on the role of the genetic component in the development of PAH, and the most common genetic mechanism is mutation in bone morphogenetic protein receptor 2 (BMPR2) [7], while the means of epigenetic alterations such as DNA methylation, noncoding RNAs, and histone methylation and acetylation in PAH are currently receiving increasing attention [89]. Fig.…”

“…EZH2 inhibits autophagic death of VSMC to suppress aortic dissection by regulating ATG5 and ATG7 expression and MEK-ERK1/2 signaling pathway. In addition, EZH2 and G9a play a critical role in pulmonary arterial smooth muscle cells to affect pulmonary arterial hypertension Excessive proliferation and resistance to apoptosis of the pulmonary artery smooth muscle cells (PASMCs) contribute to the reduction in arterial compliance and increased vascular resistance and blood pressure in PAH patients [89]. Therefore, maintaining homeostasis of PASMCs is critical for the prevention and treatment of PAH.…”

Emerging role of long non‑coding RNAs in pulmonary hypertension and their molecular mechanisms (Review)

“…Regarding the pathogenesis of the disease, PH is classified into the following five categories ( 4 ): i) pulmonary arterial hypertension (PAH); ii) left heart disease-induced PH; iii) hypoxia- or lung disease-induced PH; iv) chronic thromboembolic PH (CTEPH); and v) PH caused by unclear or multifactorial mechanisms. The pathogenesis of PH is very complex, and includes impaired angiogenesis, metabolic disorders, chronic inflammation, abnormal proliferation, and the resistance of pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) to apoptosis ( 5 ). The abnormal proliferation of VSMCs is considered to be the main cause of vascular remodeling.…”