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.
Highlights
Pulmonary hypertension (PH) is a human pathophysiological condition defined by a mean pulmonary arterial pressure ≥25 mmHg at rest
During pulmonary arterial hypertension (PAH), the pulmonary artery undergoes chronic remodeling induced by constant proliferation of pulmonary endothelial cells (EC) and increased resistance to apoptosis which leads to an occlusion of the artery and subsequent pulmonary hypertension as depicted in Figure 1 [13,14,15]
While here we focus on the three major signaling axis that are disrupted, namely the endothelial nitric oxide (NO), endothelin-1 (ET-1), and prostacyclin (PGI2) pathways [26,27,28], the contribution of other important pathways involving BMPR2/transforming growth factor beta (TGFβ) or RhoA/Rho-kinase (RhoA/ROCK) signaling have been extensively described in other reviews [29,30]
Summary
Pulmonary hypertension (PH) is a human pathophysiological condition defined by a mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest. PH can further be classified in five distinct groups, based on clinical presentation, overlapping hemodynamics and/or treatment strategies: pulmonary arterial hypertension (PAH), PH due to left heart disease, PH due to hypoxia or lung disease, PH due to chronic thromboembolism and PH due to unclear mechanisms [1]. This progressive disease is characterized by the remodeling of the pulmonary artery leading to vascular obstruction which, in turn, leads to increased blood pressure in order to preserve the blood flow [2,3]. 33% of PAH patients succumb from right heart failure (RHF), a chronic end-stage cardiac disease originating from the inability of the right ventricle (RV) to compensate for the PAH [22,24]
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