Alexander Seidinger, Richard Roberts, Yan Bai, Marion Müller, Eva Pfeil, Michaela Matthey, Sarah Rieck, Judith Alenfelder, Gabriele M. KUonig, Alexander Pfeifer, Evi Kostenis, Anna Klinke, Bernd K. Fleischmann, Daniela Wenzel
University Hospital of the Ruhr University of Bochum and Ruhr University of Bochum. University Hospital of Nottingham. Massachusetts General Hospital and Harvard Medical School. University of Bonn.
Germany, United Kingdom and United States
European Molecular Biology Organization Molecular Medicine
EMBO Mol Med 2024;
DOI: 10.1038/s44321-024-00096-0
Abstract
Pulmonary arterial hypertension (PAH) is a life-threatening disease with limited survival. Herein, we propose the pharmacological inhibition of Gq proteins as a novel concept to counteract pulmonary vasoconstriction and proliferation/migration of pulmonary artery smooth muscle cells (PASMCs) in PAH. We demonstrate that the specific pan-Gq inhibitor FR900359 (FR) induced a strong vasorelaxation in large and small pulmonary arteries in mouse, pig, and human subjects ex vivo. Vasorelaxation by FR proved at least as potent as the currently used triple therapy. We also provide in vivo evidence that local pulmonary application of FR prevented right ventricular systolic pressure increase in healthy mice as well as in mice suffering from hypoxia (Hx)-induced pulmonary hypertension (PH). In addition, we demonstrate that chronic application of FR prevented and also reversed Sugen (Su)Hx-induced PH in mice. We also demonstrate that Gq inhibition reduces proliferation and migration of PASMCs in vitro. Thus, our work illustrates a dominant role of Gq proteins for pulmonary vasoconstriction as well as remodeling and proposes direct Gq inhibition as a powerful pharmacological strategy in PH.
Category
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Medical Therapy. Efficacy or Lack of Efficacy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes