Exploring P300/CBP as therapeutic targets for pulmonary arterial hypertension and right ventricular failure

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary artery (PA) pressure and vascular remodeling, resulting in compensated hypertrophy and decompensated failure of the right ventricle (RV). The histone acetyltransferases P300/CBP are critical regulators in various cellular processes such as proliferation, apoptosis, hypertrophy, and fibrosis. Considering their pivotal role in modulating gene transcription, we hypothesized that P300/CBP contributes to maladaptive remodeling observed in PAH. Using western blot (WB) and immunofluorescence (IF), we show increased P300/CBP expression in isolated PA smooth muscle cells (PASMCs) and PAs from PAH patients compared to controls (p<0.01) as well as in monocrotaline (MCT) and sugen-hypoxia rat (p<0.05). Similarly, P300 expression is elevated in remodeled RV from PAH patients, MCT- and pulmonary artery banding- rats (PAB). In vitro, P300/CBP inhibition (CCS-1477 or siRNA) decreases PAH-PASMC proliferation and resistance to apoptosis [WB (PCNA, PLK1, Survivin) IF (Ki67, AnexinV)], prevents phenylephrine-induced hypertrophy (H9C2 cells, adult rat cardiomyocytes), and reduces activation (pSMAD2/3, aSMA, Fn, Col1A, MMP2, WB) and proliferation (PCNA, WB) of RV fibroblasts. In vivo administration of CCS-1477 in MCT rats reduces pulmonary vascular remodeling (Elastica Van Gieson), improves pulmonary hemodynamics (mPAP, RVSP) and attenuates RV fibrosis (Masson’s Trichrome (MT)). In the PAB rat model, CCS-1477 improves RV function (TAPSE, CO, SV) and reduces fibrosis (MT). Our finding suggests that targeting P300/CBP may represent a promising avenue to tackle both lung and RV maladaptive remodeling in PAH.