Combination of Orai1 inhibitor CM5480 with specific therapy mitigates pulmonary hypertension and its cardiac dysfunction

• Text
• PDF

Abstract

Pulmonary arterial hypertension (PAH) is a rare and incurable disease characterized by progressive narrowing of pulmonary arteries (PA), resulting in right ventricular (RV) hypertrophy, RV failure, and eventually death. Orai1 inhibition has emerged as promising therapeutic approach to mitigate PAH. In this study, we investigated the efficacy of a clinically applicable selective Orai1 inhibitor, CM5480, and its effects when combined with standard PAH therapies in a preclinical PAH model. In male and female monocrotaline PAH-rats, CM5480 monotherapy improved hemodynamics, PA, and RV remodeling, as confirmed by RV catheterization, echocardiography, histology, and unbiased RNA-Seq. Standard PAH therapies, ambrisentan or sildenafil, achieved modest improvements in experimental PAH. In contrast, combination therapies with CM5480 yielded significantly greater benefits in reducing PA remodeling and improving cardiac function compared with monotherapies. Furthermore, in vitro experiments showed that Orai1 knockdown reduced pulmonary endothelial cell dysfunction in PAH and that the Orai1 pathway is independent of standard PAH-targeted pathways in PA smooth muscle cells (PASMCs). Finally, we found enhanced Orai1 expression/function in PASMCs and pulmonary vein SMCs from patients with pulmonary veno-occlusive disease. These findings suggest that Orai1 inhibition represents a potentially novel and complementary therapeutic strategy for PAH by acting at pulmonary vascular and RV levels.

Authors

Anaïs Saint-Martin Willer, Grégoire Ruffenach, Bastien Masson, Kristelle El Jekmek, Angèle Boët, Rui Adão, Mathieu Gourmelon, Antoine Beauvais, Jessica Sabourin, Mary Dutheil, Maria-Rosa Ghigna, Laurent Tesson, Séverine Ménoret, Ignacio Anegon, Fabrice Bauer, Vincent de Montpréville, Sudarshan Hebbar, Carmen Brás-Silva, Kenneth Stauderman, Marc Humbert, Olaf Mercier, David Montani, Véronique Capuano, Fabrice Antigny