Abstract

Pulmonary arterial hypertension (PAH) is characterized by vascular obstruction leading to progressive elevation of pulmonary artery pressure. In the face of pressure overload, the right ventricle (RV) initially compensates (adaptive hypertrophy), but ultimately transitions to a decompensated state (marked by cardiomyocyte apoptosis and fibrosis), leading to premature death. The histone acetyltransferases P300/CBP have been identified as key pathogenic factors promoting the activation of a fetal gene program, supporting vascular remodeling in the lungs of PAH patients. Previous studies have also implicated P300/CBP in the control of pathological cardiac hypertrophy and fibrosis. However, their role in RV failure associated with PAH has never been explored. We hypothesized that P300/CBP contribute to maladaptive RV remodeling in PAH and thus represent a potential therapeutic target. We show by Western blot (WB) and immunofluorescence (IF) that P300 expression is upregulated in compensated and decompensated RV from PAH patients, monocrotaline (MCT)- and pulmonary artery banding (PAB)-exposed rats (p<0.05), whereas CBP expression remains unchanged. RV fibroblasts (RVfbs) isolated from compensated or decompensated RV display a pro-fibrotic phenotype (increased COL, Fn, MMP and aSMA expression, WB p<0.05) associated with an increase in P300/CBP expression (WB, p<0.01). In vitro, pharmacological (CCS-1477) or molecular (combined siRNA) inhibition of P300/CBP decreases proliferation/survival (WB PCNA, Survivin, p<0.05) and activation (WB pSMAD2/3, aSMA, Fn, Col1, MMP2, p<0.05) of RVfibs. These effects were associated with a reduction in H3K27 acetylation (WB, p<0.05). In addition, P300/CBP inhibition prevents phenylephrine-induced hypertrophy in H9C2 cells and in isolated adult rat cardiomyocytes (IF, p<0.05). Using human precision-cut RV slices stimulated with phenylephrine and TGFb, we show that P300/CBP inhibition attenuates fibrosis [Masson’s trichrome staining (MT), p<0.05] and cardiomyocyte (CM) hypertrophy [hematoxylin and eosin staining (HE), p<0.05]. In vivo, administration of CCS-1477 in a PAB rat model reduces fibrosis (MT, p<0.05), CM surface area (HE, p<0.01), and improves RV function (TAPSE, cardiac output, stroke volume, p<0.05). Our finding provide evidence that targeting P300/CBP may represent a promising avenue to counter maladaptive RV remodeling in PAH.