Implication of Integrin α5β1 in right ventricular failure associated with pulmonary arterial hypertension

Right ventricular (RV) function is an important prognosis factor in pulmonary arterial hypertension (PAH). In response to pressure overload, the RV undergoes morphological changes driven by the accumulation of extracellular matrix (ECM) elements and cardiomyocyte hypertrophy. Integrins (ITG) are members of the cell adhesion receptors superfamily. Through ECM-binding, ITG are known to transduce extracellular cues to cardiac cells resulting in the activation of pro-hypertrophic and pro-fibrotic signaling pathways. Among them, ITGα5β1 is one of the most abundant heterodimers in cardiac tissue. We thus hypothesized that ITGα5β1 signaling promotes pathological RV remodeling. Using Western Blot (WB), we found elevated levels of ITGα5 and ITGβ1 in RV isolated from PAH patients compared to controls. Similar findings were observed in monocrotaline (MCT) and pulmonary artery banding (PAB) rats. In adult rat cardiomyocytes, pharmacological inhibition of ITGα5β1 decreased phenylephrine (PE)-induced hypertrophy (f-actin labeling). Inhibition of ITGα5β1 decreased proliferation and activation of PAH-RVFbs (WB PCNA, αSMA, COL1; Ki67). <italic>In vivo</italic>, inhibition of ITGα5β1 improved RV dysfunction (CO, TAPSE, RVFAC) and diminished RV hypertrophy and fibrosis (Fulton index, H&E and Masson’s trichrome) in MCT rats with established PAH. In the PAB rat model, inhibition of ITGα5β1 attenuated RV dysfunction (CO, TAPSE, RVFAC as assessed by echocardiography, RHC and cardiac MRI). <italic>Ex vivo</italic>, inhibition of ITGα5β1 attenuated cardiomyocyte hypertrophy and RV fibrosis in human precision-cut RV slices exposed to PE and TGFβ1. Our results suggest that integrins play a key role in pathological RV remodeling in PAH.