Identification of integrin a5b1 inhibition as a potentially disease-modifying approach for the treatment of pulmonary arterial hypertension

Le résumé fourni par la source

Pulmonary arterial hypertension (PAH) is characterized by pathogenic remodeling of the distal arteries arising from pulmonary arterial smooth muscle cell (PASMC) hyperplasia, pulmonary arterial endothelial cell (PAEC) dysfunction, and increased deposition of extracellular matrix (ECM). Given the central role of the ECM in the restructuring of vasculature, we investigated the potential to therapeutically target a5b1, a fibronectin-binding integrin implicated in cell proliferation and angiogenesis, for PAH. Immunohistochemical analysis of lungs from PAH patients revealed increased fibronectin and a5b1 expression in distal pulmonary arteries. To assess the function of a5b1, we have developed potent, orally bioavailable, small molecule inhibitors (SMi) and monoclonal antibodies (mAb) targeting a5b1. Selective inhibition of a5b1 in cultured PASMC modulated multiple pathways involved in cell cycle regulation at a transcriptional and post-transcriptional level and blocked cellular proliferation. Human precision cut lung slices (PCLS) treated with a5b1 inhibitors decreased expression of pathways involved in ECM deposition and decreased levels of smooth muscle cell markers. Finally, a5b1 inhibition with either a SMi or mAb significantly improved cardiac and vascular function in the rat Sugen/hypoxia PAH model by reducing pulmonary arterial wall thickness, right ventricular hypertrophy, and fibrosis. These data highlight a hitherto unappreciated role for a5b1 in the pathogenesis of PAH and support the potential for a5b1 inhibition as a disease-modifying therapeutic strategy for the management of PAH.

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