| Autor: |
Seidinger, Alexander, Roberts, Richard, Bai, Yan, Müller, Marion, Pfeil, Eva, Matthey, Michaela, Rieck, Sarah, Alenfelder, Judith, König, Gabriele M, Pfeifer, Alexander, Kostenis, Evi, Klinke, Anna, Fleischmann, Bernd K, Wenzel, Daniela |
| Zdroj: |
EMBO Molecular Medicine; Aug2024, Vol. 16 Issue 8, p1930-1956, 27p |
| Abstrakt: |
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. Synopsis: This study highlights the decisive role of Gq proteins in pulmonary vasoconstriction and vascular remodeling, the main hallmarks of pulmonary hypertension (PH), and introduces the pharmacological pan-Gq inhibitor FR900359 (FR) as a potential therapeutic compound. Gq inhibition by FR induced strong pulmonary vasorelaxation in mice, pigs, and humans ex vivo. Gq inhibition by FR reduced cell growth and migration of pulmonary artery smooth muscle cells in vitro. FR prevented and reversed hypoxia-induced PH in mice in vivo. This study highlights the decisive role of Gq proteins in pulmonary vasoconstriction and vascular remodeling, the main hallmarks of pulmonary hypertension (PH), and introduces the pharmacological pan-Gq inhibitor FR900359 (FR) as a potential therapeutic compound. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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