Article Impact Level: HIGH Data Quality: STRONG Summary of EMBO Molecular Medicine. https://doi.org/10.1038/s44321-024-00096-0 Dr. Alexander Seidinger et al.
Points
- The study presents the pharmacological inhibition of Gq proteins as a novel approach for treating pulmonary arterial hypertension (PAH), a disease characterized by intense pulmonary vasoconstriction and the proliferation of pulmonary artery smooth muscle cells (PASMCs).
- The pan-Gq inhibitor FR900359 (FR) demonstrated significant vasorelaxation effects in pulmonary arteries of mice, pigs, and humans in ex vivo studies, showing potential to match or exceed the results of current triple therapies used in PAH treatment.
- In vivo experiments revealed that local application of FR in the lungs effectively prevented an increase in right ventricular systolic pressure in both healthy and hypoxia-induced pulmonary hypertensive mice, suggesting its usefulness as both a preventative and therapeutic agent.
- FR significantly reduced the proliferation and migration of PASMCs in vitro, indicating that Gq proteins are central to the mechanisms of vasoconstriction and vessel remodeling in PAH.
- This research advocates direct inhibition of Gq proteins as a powerful pharmacological strategy, offering a new promising avenue for intervention in PAH, a disease with limited treatment options and high mortality.
Summary
The study introduces the pharmacological inhibition of Gq proteins as a groundbreaking strategy for treating pulmonary arterial hypertension (PAH), a disease characterized by severe pulmonary vasoconstriction and proliferation/migration of pulmonary artery smooth muscle cells (PASMCs). Employing the specific pan-Gq inhibitor FR900359 (FR), researchers observed significant vasorelaxation effects in both large and small pulmonary arteries across mice, pigs, and human subjects in ex vivo settings. The vasorelaxation induced by FR was comparable, if not superior, to the effects observed with the current triple therapy used in clinical settings, demonstrating its potential efficacy.
Further, in vivo experiments underscored the therapeutic benefits of FR, revealing that local pulmonary application of the inhibitor effectively prevented an increase in right ventricular systolic pressure in healthy mice and those suffering from hypoxia-induced pulmonary hypertension (PH). More impressively, chronic application of FR prevented and reversed PH induced by Sugen-hypoxia (SuHx) in mice. These findings highlight FR’s potential as a preventative and therapeutic agent in managing the progression of PAH.
Additionally, the study demonstrated that Gq inhibition significantly reduces the proliferation and migration of PASMCs in vitro, supporting the hypothesis that Gq proteins play a critical role in pulmonary vasoconstriction and vessel remodeling associated with PAH. Overall, the research supports the direct inhibition of Gq proteins as a potent pharmacological approach in treating PH, offering a promising new avenue for interventions in a disease with limited current treatment options and high mortality rates.
Link to the article: https://www.embopress.org/doi/full/10.1038/s44321-024-00096-0
References Seidinger, A., Roberts, R., Bai, Y., Müller, M., Pfeil, E., Matthey, M., Rieck, S., Alenfelder, J., König, G. M., Pfeifer, A., Kostenis, E., Klinke, A., Fleischmann, B. K., & Wenzel, D. (2024). Pharmacological Gq inhibition induces strong pulmonary vasorelaxation and reverses pulmonary hypertension. EMBO Molecular Medicine. https://doi.org/10.1038/s44321-024-00096-0
