Fig. 3

Epigenetic modifications and potential therapeutic targets for PAH. Epigenetic modifications such as DNA methylation, histone acetylation, and methylation play crucial roles in PAH. Increased HDAC activity in PAH represses the expression of genes involved in vasodilation and angiogenesis. EZH2, a histone methyltransferase enzyme that catalyzes the methylation of lysine 27 on histone H3, is also implicated in PAH pathogenesis. Furthermore, the epigenetic reader BRD4 is a transcriptional co-activator that binds to acetylated lysine residues on histone proteins and facilitates recruitment of transcriptional machinery to target genes. Additionally, DNMT1, TET1, and TET2 dysregulation induces aberrant DNA methylation patterns that contribute to the development and progression of PAH. Targeting epigenetic modifications with drugs such as BET (JQ1, apabetalone [RVX-208]), DNMT (5ʹ-aza-2ʹdeoxycytidine, decitabine), HDAC (SAHA, VPA, MGCD0103, MS-275), and EZH2 (tazemetostat, GSK126) inhibitors has shown promise as potential therapies for PAH by reversing the hyperproliferative and anti-apoptotic phenotypes of cells in the pulmonary vasculature. DNMT DNA methyltransferase, TET ten-eleven translocation methylcytosine dioxygenase, BRD4 bromodomain-containing protein 4, EZH2 enhancer of zeste homolog 2, HDAC Histone Deacetylase, H3K27me3 histone 3 lysine 27 trimethylation, Me methylation, Ac acetylation, SAHA suberoylanilide hydroxamic acid, VPA valproic acid. Created with BioRender.com