Increased DNA Methylation: A Potential Therapeutic Target in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is marked by vasoconstriction and remodeling of pulmonary arteries, driven by excessive proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). This contributes to disease progression, with current treatments showing limited success. DNA methylation (DNAm) has been linked to pro-proliferative and survival phenotypes, suggesting its role in PAH. We hypothesized that increased DNAm contributes to the survival and proliferation of PASMCs in PAH, positing DNAm targeting could offer therapeutic benefits. We observed a global DNAm increase and elevated DNA methyltransferase levels in PASMCs from PAH patients and in three preclinical models (monocrotaline, sugen hypoxia, Fawn hooded rats), indicating a potential mechanism for disease exacerbation. In vitro, PAH-PASMCs showed elevated DNAm and DNA methyltransferase levels, with reduced DNA demethylase expression. Treatment with the hypomethylating agent Zebularine led to dose-dependent reductions in PASMC proliferation and increased apoptosis, supported by transcriptomic analyses suggesting involvement of cell cycle and mitosis regulation. In vivo, Zebularine treatment improved PAH hemodynamics, decreased PASMC methylation and proliferation, and reduced vascular remodeling in rodent models, highlighting the drug's potential for reversing PAH pathology. Our research links increased DNAm with PAH progression and suggests targeting DNAm, as demonstrated by Zebularine's efficacy, could be a promising therapeutic strategy, addressing underlying molecular alterations and offering hope for more effective treatments.