Targeting alpha 5 beta 1 integrin as a therapeutic strategy to combat right ventricular dysfunction in pulmonary arterial hypertension

Introduction 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 are members of the cell adhesion receptor superfamily. Through ECM-binding, integrins are known to transduce extracellular cues to cardiac cells resulting in the activation of pro-hypertrophic and pro-fibrotic signaling pathways. Among them, integrin α5β1 is one of the most abundant heterodimers in cardiac tissue. We hypothesized that α5β1 signaling promotes pathological RV remodeling. Methods & Results Using Western blot (WB), we found elevated levels of integrins α5 and β1 protein in RV isolated from PAH patients compared to controls. Its expression level correlated with the severity of RV dysfunction. Similar findings were observed in monocrotaline (MCT) and pulmonary artery banding (PAB) rats. In adult rat cardiomyocytes, pharmacological inhibition of α5β1 decreased phenylephrine-induced hypertrophy and reversed established hypertrophy induced by MCT treatment (assessment of cell surface area by F-actin labeling). In human RV fibroblasts (RVFB) inhibition of α5β1 prevented TGFβ1-induced activation of control RVFB and decreased proliferation and activation of RVFB derived from PAH patients (WB PCNA, αSMA, COL1; immunofluorescence Ki67). In pulmonary artery banding rats, α5β1-neutralizing antibody (mAB4) alone or in combination with sotatercept improves RV dysfunction (CO, TAPSE, RV strain; assessed by echocardiography, RHC and cardiac MRI) and diminished RV hypertrophy and fibrosis (Fulton index, H&E and Masson’s trichrome staining). Ex vivo, inhibition of α5β1 attenuated cardiomyocyte hypertrophy and RV fibrosis in human precision-cut RV slices exposed to phenylephrine and TGFβ1. Conclusion Our results suggest that integrin α5β1 plays a key role in pathological RV remodeling in PAH.