Pulmonary arterial hypertension (PAH) is defined by increased pulmonary artery (PA) pressure and vascular remodeling, leading to progressive hypertrophy (compensation) and failure (decompensation) of the right ventricle (RV). The histone acetyltransferases P300/CBP have been identified as central players in various cellular processes (proliferation/apoptosis and hypertrophy/fibrosis). Given their role in controlling gene transcription programs, we hypothesized that P300/CBP contributes to maladaptive remodeling in PAH.

We show by western blot (WB) and immunofluorescence (IF) increased P300/CBP expression in isolated PA smooth muscle cells (PASMCs) and distal PAs from PAH patients compared to controls (p<0.01) as well as in monocrotaline (MCT) and sugen-hypoxia rat models (p<0.05). Similarly, P300 expression is up-regulated in remodeled RV from PAH patients, MCT- and pulmonary artery banding-subjected rats (WB). In vitro, P300/CBP inhibition (CCS-1477 or siRNA) decreases PAH-PASMC proliferation and resistance to apoptosis [WB (PCNA, PLK1, Survivin) IF (Ki67, AnexinV), p<0.01], prevents phenylephrine-induced hypertrophy (H9C2 cells, adult rat cardiomyocytes, p<0.05), and reduces activation (pSMAD2/3, aSMA, Fn, Col1A, MMP2) and proliferation (PCNA, Survivin) of activated RV fibroblasts. In vivo, administration of CCS-1477 reduces pulmonary vascular remodeling (Elastica Van Gieson, p<0.05), improves pulmonary hemodynamics (p<0.01) and attenuates RV fibrosis (Masson?s Trichrome, p<0.05) in MCT rats with established PAH.

Our finding provide evidence that targeting P300/CBP may represent a promising avenue to tackle both lung and RV maladaptive remodeling in PAH.