Abstract

BACKGROUND: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by persistent elevation of pulmonary arterial (PA) pressure, which results in a striking increase in right ventricular (RV) afterload and subsequent failure. PA smooth muscle cells (PASMCs) from PAH patients exhibit a cancer-like hyperproliferative and apoptosis-resistant phenotype contributing to obliteration of the vascular lumen. 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 and is critical for cancer cell proliferation and survival. Thus, we hypothesized that EZH2 expression is up-regulated in PAH-PASMCs leading to vascular remodeling in PAH.

AIM:  We aim to demonstrate that up-regulation of EZH2 in PAH-PASMCs promotes vascular remodeling in PAH.

METHODS AND RESULTS: Using Western blot (WB), we showed that EZH2 is upregulated in lungs, distal PAs and isolated PASMCs from PAH patients (p<0.01) compared to controls. EZH2 expression was also increased in human compensated RV but was decreased in PAH patients with decompensated RV failure. Similar results were found in the monocrotaline (MCT) rat model. Pharmacological (GSK126 or EPZ-6438) or molecular (siEZH2) 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). This effect was associated with decreased expression of Survivin (WB, p<0.05).

CONCLUSION: We provide evidence that EZH2 is implicated in PAH and contributes to the cancer-like phenotype of PAH-PASMCs.