Implication of Enhancer of Zeste Homolog 2 in Pulmonary Arterial Hypertension

Abstract

Background: Pulmonary arterial hypertension (PAH) is characterized by persistent elevation of pulmonary arterial (PA) pressure due to excessive proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). Right ventricular (RV) failure is the cause of mortality associated with PAH, and is associated with maladaptive RV remodeling and fibrosis. Although epigenetic modifications are increasingly appreciated as an important contributing factor of PAH development, the precise mechanisms remain to be elucidated. EZH2 is a histone methyltransferase that is overexpressed in many cancers promoting cell proliferation and survival.

Aim: Study the role of EZH2 in PAH progression.

Methods and Results: Using Western blot (WB), we demonstrated that EZH2 is overexpressed in lungs, distal PAs and isolated PASMCs from PAH patients (p<0.01) as well as in the monocrotaline (MCT) and Sugen/Hypoxia rat models (p<0.05). Pharmacological or molecular inhibition of EZH2 leads to reduced PAH-PASMC proliferation (Ki67 labeling and EdU assay, p<0.001) and resistance to apoptosis (Annexin V assay p<0.001). These effects were accompanied by the expression changes of proteins associated with metabolism. In addition, we found that EZH2 is increased in human compensated RV but was decreased in PAH patients with decompensated RV failure (WB, p<0.05). Similar results were found in the MCT model in which the progression of RV remodeling was divided into 4 stages based on hemodynamic data.

Conclusion: We demonstrated that EZH2 is implicated in PAH. Further research is required to understand precisely the role of EZH2 in lung and cardiac remodeling in the setting of PAH.