Abstract
Pulmonary arterial hypertension (PAH) is a disease that progress over time and is defined as an increase in pulmonary arterial pressure and pulmonary vascular resistance that frequently leads to right-ventricular (RV) failure and death. Epigenetic modifications comprising DNA methylation, histone remodeling, and noncoding RNAs (ncRNAs) have been established to govern chromatin structure and transcriptional responses in various cell types during disease development. However, dysregulation of these epigenetic mechanisms has not yet been explored in detail in the pathology of pulmonary arterial hypertension and its progression with vascular remodeling and right-heart failure (RHF). Targeting epigenetic regulators including histone methylation, acetylation, or miRNAs offers many possible candidates for drug discovery and will no doubt be a tempting area to explore for PAH therapies. This review focuses on studies in epigenetic mechanisms including the writers, the readers, and the erasers of epigenetic marks and targeting epigenetic regulators or modifiers for treatment of PAH and its complications described as RHF. Data analyses from experimental cell models and animal induced PAH models have demonstrated that significant changes in the expression levels of multiple epigenetics modifiers such as HDMs, HDACs, sirtuins (Sirt1 and Sirt3), and BRD4 correlate strongly with proliferation, apoptosis, inflammation, and fibrosis linked to the pathological vascular remodeling during PAH development. The reversible characteristics of protein methylation and acetylation can be applied for exploring small-molecule modulators such as valproic acid (HDAC inhibitor) or resveratrol (Sirt1 activator) in different preclinical models for treatment of diseases including PAH and RHF. This review also presents to the readers the application of microfluidic devices to study sex differences in PAH pathophysiology, as well as for epigenetic analysis.
Highlights
Since gene expression is governed by miRNAs via a decrease in the translation of target mRNAs, they play a major role in Pulmonary arterial hypertension (PAH), a disease that is characterized by excessive proliferation and resistance to apoptosis of pulmonary arterial smooth muscle cells (PASMCs), pulmonary arterial endothelial cells (PAECs), and pulmonary arterial adventitial cells (PAADCs)
Microfluidic chip model mimicking the PAH-afflicted artery could mimic the hormone response in a similar fashion to that observed in PAH patients
This study suggests that the newly developed PAH tissue chip model responds to hormones in a similar fashion to that observed in PAH patients, and that it is a useful model for studying the mechanism of sex disparity to develop sex-specific therapies for patients with PAH, and epigenetic modulators such as sirtuin activators to develop new targets for PAH therapy
Summary
Pulmonary arterial hypertension (PAH) or group 1 pulmonary hypertension (PH) is a disease characterized by an increase in pulmonary arterial pressure and pulmonary vascular resistance that often leads to right-sided heart failure and death. The PAH prevalence in Europe was reported to range from 15–52 per million [3]; Scottish prevalence was 26 cases per million population [4], and the French PAH registry revealed 26 cases per million individuals [5,6] This discrepancy might be attributed to differences in the prevalence of associated diseases with PAH among these countries and other variations including period and geographic area, genetic background, and pharmacologic treatment availability [7]. The pathology of PAH is coordinated with many molecular mechanisms including genetic and epigenetic dysregulation, apoptosis resistance and dysfunction of pulmonary arterial endothelial cells (PAECs), increased proliferation of pulmonary arterial smooth muscle cells (PASMCs), inflammation, DNA damage, metabolic diseases, sex hormone disorders, and oxidative stress [11] (Figure 1). Asasa progression consequence,ofplexiform lesions and vessel occlusion cause reduced blood flow, resulting in PAH as progression of PAH
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