Epigenetic Regulation of Pulmonary Arterial Hypertension-Induced Vascular and Right Ventricular Remodeling: New Opportunities?

Abstract

Pulmonary artery hypertension (PAH) is a rare chronic disease with high impact on patients’ quality of life and currently no available cure. PAH is characterized by constant remodeling of the pulmonary artery by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), fibroblasts (FBs) and endothelial cells (ECs). This remodeling eventually leads to increased pressure in the right ventricle (RV) and subsequent right ventricle hypertrophy (RVH) which, when left untreated, progresses into right ventricle failure (RVF). PAH can not only originate from heritable mutations, but also develop as a consequence of congenital heart disease, exposure to drugs or toxins, HIV, connective tissue disease or be idiopathic. While much attention was drawn into investigating and developing therapies related to the most well understood signaling pathways in PAH, in the last decade, a shift towards understanding the epigenetic mechanisms driving the disease occurred. In this review, we reflect on the different epigenetic regulatory factors that are associated with the pathology of RV remodeling, and on their relevance towards a better understanding of the disease and subsequently, the development of new and more efficient therapeutic strategies.

Transgenerational inheritance of promoter methylation changes in extrauterine growth restriction-induced pulmonary arterial pressure disorders

“…During PAH, the pulmonary artery undergoes chronic remodeling induced by constant proliferation of pulmonary endothelial cells and increased resistance to apoptosis which leads to an occlusion of the artery and subsequent pulmonary hypertension. It is not a surprise that chromatin remodeling has also been studied in the context of PAH (15). For example, HDAC class I activity was shown to increase during hypoxia induced but in vivo HDAC inhibition resulted in decreased pulmonary remodeling during PAH (16).…”

Epigenetic Mechanisms as Emerging Therapeutic Targets and Microfluidic Chips Application in Pulmonary Arterial Hypertension

“…The expression of miRNA is one of the major mechanisms for epigenetic regulation [ 163 , 164 ]. Since gene expression is governed by miRNAs via a decrease in the translation of target mRNAs, they play a major role in PAH, a disease that is characterized by excessive proliferation and resistance to apoptosis of PASMCs, PAECs, and pulmonary arterial adventitial cells (PAADCs).…”

Role of Long Non-Coding RNAs in Pulmonary Arterial Hypertension

“…In PAH, the RV endures complex remodeling, including RV pressure overload, changes in myocardial extracellular matrix, and an increase in cardiomyocyte size, and enhanced capillary angiogenesis and intrinsic contractility [95]. As a result of prolonged pressure overload, adaptive response gradually changes into maladaptive remodeling and eventually leads to RV failure and death.…”