Role and regulation of Jumonji C domain-containing histone demethylases 1A and 2B in pulmonary hypertension

Pulmonary hypertension (PH) is characterized by increased proliferation and apoptosis resistance of pulmonary vascular cells. Jumonji C domain-containing histone demethylases (JMJDs) are a novel class of epigenetic regulators, implicated in chromatin regulation and often possess the ability to demethylate lysine residues on histones. Given that the JMJDs and the histone methylation level is important for the proliferative capacity of cancer cells, we postulated the contribution of JMJDs to excessive vascular remodeling underlying PH. Expression of JMJDs was analyzed in vascular cells exposed to hypoxia. Increased expression of JMJD1A and JMJD2B were observed in all three cell types. Increased nuclear localization and activity of JMJD1A and JMJD2B were observed in hypoxic PASMCs. Increased expression of JMJD1A and JMJD2B was dependent on hypoxia induced factor 1α (HIF1α). Importantly, selective knockdown of these JMJDs by siRNA and JMJD inhibitors led to inhibition of proliferation and induction of apoptosis in vascular cells exposed to hypoxia. Furthermore, in laser micro-dissected vessels and pulmonary arteries from idiopathic pulmonary arterial hypertension (IPAH) patients, increased expression of JMJD1A and JMJD2B was observed compared to donors. Next generation RNA-sequencing of hypoxia treated PASMCs with JMJD1A and JMJD2B knockdown lead to identification of promising JMJD target genes, which are involved in biological processes like proliferation (MKI67), apoptosis (BCL2, BIRC5), metabolism (LDHA, TK1) and inflammation (CCR7, CCL3). In conclusion, our results suggest that JMJDs are regulated in PH vasculature and play an important role in PH pathogenesis.