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

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.

Transcription factors in the pathogenesis of pulmonary arterial hypertension—Current knowledge and therapeutic potential

“…In the pulmonary vasculature, it is thus necessary (a) to fully understand the underlying epigenetic mechanisms that facilitate three-dimensional chromatin conformation and accessibility and (b) how exactly epigenetic modifications affect TF networks. This is especially important in light of epigenetic modifiers emerging as druggable targets in PAH (224,225).…”

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

“…Third, epigenetic modifications and PTMs of targets that induce or inhibit ferroptosis have been identified, and dysregulated epigenetic modifications and PTMs can be feasibly targeted by small molecule compounds. Epigenetic drugs have exhibited viable therapeutic potential for NSDs, 607 – 610 CVDs, 611 – 615 liver diseases, 616 , 617 lung diseases, 618 – 620 and kidney diseases 621 – 623 in preclinical and clinical trials. Epigenetic drugs targeting epigenetic regulators through modulation of epigenetic mechanisms have been applied and clinically translated for the treatment of hematological malignancies, greatly contributing to the development of antitumor drugs.…”

MicroRNA and lncRNA as the Future of Pulmonary Arterial Hypertension Treatment

“…Discussion of all these mechanisms is beyond the scope of this article; therefore, in this paper, we focus on discussing the role of non-coding RNA in the development of PAH. Unlike mRNAs, ncRNAs are not encoded for proteins or peptides and include siRNAs, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and extracellular RNAs [41]. An example of a substance used in cardiology whose mechanism is based on siRNA is inclisiran, a drug used in hypercholesterolemia [42,43].…”

“…In vertebrae, over 50% of protein coding mRNA is controlled by miRNA [46]. The expression of proteins is silenced by miRNA binding to specific mRNAs, thus playing a fundamental role in the post-transcriptional regulation of gene expression [41,45]. Different miRNAs participate in the processes of differentiation, apoptosis, and cell proliferation; hence, the dysregulation of the expression or activity of these RNAs results in a disturbance in cellular homeostasis, which consequently can lead to numerous diseases, such as PAH [47].…”