Epigenetic mechanisms in pulmonary arterial hypertension: the need for global perspectives

Abstract

Pulmonary arterial hypertension (PAH) is a severe and progressive disease, characterised by high pulmonary artery pressure that usually culminates in right heart failure. Recent findings of alterations in the DNA methylation state of superoxide dismutase 2 and granulysin gene loci; histone H1 levels; aberrant expression levels of histone deacetylases and bromodomain-containing protein 4; and dysregulated microRNA networks together suggest the involvement of epigenetics in PAH pathogenesis. Thus, PAH pathogenesis evidently involves the interplay of a predisposed genetic background, epigenetic state and injurious events. Profiling the genome-wide alterations in the epigenetic mechanisms, such as DNA methylation or histone modification pattern in PAH vascular cells, may explain the great variability in susceptibility and disease severity that is frequently associated with pronounced remodelling and worse clinical outcome. Moreover, the influence of genetic predisposition and the acquisition of epigenetic alterations in response to environmental cues in PAH progression and establishment has largely been unexplored on a genome-wide scale. In order to gain insights into the molecular mechanisms leading to the development of PAH and to design novel therapeutic strategies, high-throughput approaches have to be adopted to facilitate systematic identification of the disease-specific networks using next-generation sequencing technologies, the application of these technologies in PAH has been relatively trivial to date. @ERSpublications An epigenetic component is hypothesised in PAH: an overview of the current literature and future perspectives

DNA Methylation and Histone Modification in Hypertension

“…While numerous studies have outlined the epigenetic mechanisms in pulmonary hypertension (reviewed in [ 56 , 57 , 58 , 59 ]), the epigenomic regulation in systemic hypertension remains largely undescribed. Due to the well-known involvement of the renin-angiotensin-aldosterone system (RAAS) system on arterial pressure regulation, the effects of epigenomic regulation of the RAAS system have been extensively tested in animal models of systemic hypertension [ 4 ].…”

MiR-125a-5p ameliorates monocrotaline-induced pulmonary arterial hypertension by targeting the TGF-β1 and IL-6/STAT3 signaling pathways

“…MicroRNAs (miRNAs) are endogenous small noncoding RNAs (∼22 nt) that negatively regulate gene expression by binding to the 3′ untranslated region (3′-UTR) of their target coding mRNA to inhibit expression by blocking translation and/or accelerating mRNA degradation 3 . A growing number of studies have reported that specific miRNAs can improve the outcome of PAH, suggesting that miRNAs may play a role in the pathogenesis of PAH 4 , 5 . Recent studies have shown that the miR-125a-5p plays a key role in several regulatory processes, including the proliferation, migration, and apoptosis of various cell types, thereby affecting the development of certain diseases.…”

Clinical Presentation with High Penetrance in a Korean Family with Pulmonary Arterial Hypertension Associated with a BMPR2 Intron 3 Splice Site Pathogenic Variant

“…Anticipation might be explained by cumulative genetic damage or by some other mechanism besides a trinucleotide repeat. Recent work suggests a role for epigenetic, such as DNA methylation, in the pathogenesis of PAH [14]. In ammatory and hypoxic milieu might in ict oxidative damage to DNA.…”