The Fibronectin-Binding Integrins System as a Contributor to PAH Pathogenesis

作者：Sarah‐Eve Lemay, Mónica S. Montesinos, Yann Grobs, Tetsuro Yokokawa, Tsukasa Shimauchi, Sandra Breuils‐Bonnet, Sandra Martineau, Alice Bourgeois, Mabrouka Salem, Charlie Théberge, Reem El Kabbout, Charlotte Romanet, Min Lü, Xinqiang Huang, James J. Dowling, Adrian S. Ray, François Potus, Steeve Provencher, Olivier Boucherat, Sébastien Bonnet · 年份：2023 · DOI：10.1183/13993003.congress-2023.pa453 · 被引用次数：2 · 研究领域：Cell Adhesion Molecules Research、Pulmonary Hypertension Research and Treatments、Protease and Inhibitor Mechanisms

Pulmonary arterial hypertension (PAH) is characterized by the narrowing of pulmonary arteries (PAs), causing right ventricular (RV) failure and premature death. Pulmonary artery smooth muscle cells (PASMCs) from PAH patients exhibit increased proliferation and resistance to apoptosis in response to extracellular matrix remodeling. Integrins are known to be involved in all these processes. Our hypothesis is that integrin signaling promotes PASMCs proliferation and apoptosis resistance, leading to PA remodeling, RV maladaptive hypertrophy and fibrosis, resulting in RV failure in PAH. Using NanoString, we identified members of the fibronectin-binding integrins (FnBIs) family as the most abundantly expressed in PAH-PASMCs. We confirmed the changes in FnBIs expression levels by Western blot (WB) in distal PAs, PASMCs and decompensated RVs from PAH patients compared to controls. Pharmacological inhibition of FnBIs decreased PAH-PASMCs proliferation (WB PLK1; Ki67), resistance to apoptosis (WB Survivin; Annexin V) and was associated with a decreased activation of FnBIs downstream signaling pathways FAK and ILK. In adult rat cardiomyocytes and human RV fibroblasts (RVFbs), FnBIs inhibition decreased phenylephrine-induced hypertrophy (f-actin labelling) and TGFβ1-induced RVFbs activation (WB αSMA, COL1). In both monocrotaline and sugen/hypoxia rats, pharmacological inhibition of FnBIs alone or in combination with macitentan and tadalafil improved RV function (mPAP, CO, TAPSE) and vasc...