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

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.

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Publication Details

Journal
JCI Insight
Published
2025-11-09
DOI
https://doi.org/10.1172/jci.insight.191780
Citations
2
Primary Topic
Pulmonary Hypertension Research and Treatments
Type
article
Field-Weighted Citation Impact
3.04
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article

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

Bastien Masson, Vincent de Montpréville, Laurent Tesson, Fabrice Bauer et al.
2 citations
JCI Insight
Pulmonary Hypertension Research and Treatments
3.04
article

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

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

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.

JCI InsightVol. 10(21)
Universidad Complutense de Madrid (ES), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Paris-Saclay (FR), Hospital General Universitario Gregorio Marañón (ES), Hospital de São João (PT), Assistance Publique – Hôpitaux de Paris (FR), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (ES), Hypertension pulmonaire : physiopathologie et innovation thérapeutique (FR), Hôpital Marie Lannelongue (FR), CalciMedica (United States) (US), Laboratory Signaling and Cardiovascular Pathophysiology (FR), Bicêtre Hospital (FR), Nantes Université (FR)
Openalex Percentile: Top 7%
Pulmonary Hypertension Research and Treatments
3.04
DOIOpen Access PDFOpenAlex
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