1. Forskolin is an effective therapeutic small molecule for the treatment of hypertrophic cardiomyopathy through ADCY6/cAMP/PKA pathway.
- Author
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Wang W, Xue Y, Li D, Shao C, Wu K, Sun N, and Chen Q
- Subjects
- Animals, Mice, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Disease Models, Animal, Male, Mice, Inbred C57BL, Humans, Cardiomyopathy, Hypertrophic drug therapy, Cardiomyopathy, Hypertrophic metabolism, Cardiomyopathy, Hypertrophic genetics, Cyclic AMP metabolism, Colforsin pharmacology, Colforsin therapeutic use, Adenylyl Cyclases metabolism, Cyclic AMP-Dependent Protein Kinases metabolism, Signal Transduction drug effects
- Abstract
Hypertrophic cardiomyopathy (HCM) arises from a pathogenic variant in the gene responsible for encoding the myocardium-associated protein. Forskolin (FSK), a labdane diterpene isolated from Sphingomonas capillaris, exhibits diverse pharmacological effects, including bronchospasm relief, intraocular pressure reduction, and glaucoma treatment. However, whether FSK could regulate HCM and its associated mechanism remains unclear. Here, we discovered that FSK could mitigate cardiac hypertrophy in two HCM mouse models (Myh6
R404Q and Tnnt2R109Q ) in vivo. Additionally, FSK could prevent norepinephrine (NE)-induced cardiomyocyte hypertrophy in vitro. It reversed cardiac dysfunction, reduced enlarged cell size, and downregulated the expression of hypertrophy-related genes. We further demonstrated that FSK's mechanism in alleviating HCM relied on the activation of ADCY6. In conclusion, our findings demonstrate that FSK alleviates hypertrophic cardiomyopathy by modulating the ADCY6/cAMP/PKA pathway, suggesting that FSK holds promise as a therapeutic agent for HCM., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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