1. Discovery of SIRT1-Activating Hydrogen Sulfide Donating Derivatives for Efficient Resistant of Myocardial Ischemic Injury.
- Author
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Wang S, Feng D, Wang W, Zheng C, Liang C, Li S, Li H, Xu F, Cao H, Hua H, Cheng M, and Li D
- Subjects
- Animals, Apoptosis drug effects, Male, Mice, Humans, Oxidative Stress drug effects, Cardiotonic Agents pharmacology, Cardiotonic Agents chemical synthesis, Cardiotonic Agents chemistry, Mice, Inbred C57BL, Structure-Activity Relationship, Rats, Signal Transduction drug effects, Drug Discovery, Sirtuin 1 metabolism, Hydrogen Sulfide metabolism, Hydrogen Sulfide pharmacology, Hydrogen Sulfide chemistry, Myocardial Ischemia drug therapy, Myocardial Ischemia metabolism, Myocardial Ischemia pathology, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism
- Abstract
Activating SIRT1 or promoting SIRT1 expression are both protective against myocardial ischemia. Combining these approaches would be an effective strategy for treating ischemic heart disease. Herein, we identified lead compounds with SIRT1 activation activity through screening the natural product library, and five series of H
2 S donating derivatives were designed and synthesized. Among them, compound 17 exerted an effective cardioprotective effect in vitro and in vivo . The addition of H2 S scavenger attenuated the protective activity, emphasizing the critical involvement of H2 S in the myocardial ischemia process. Interestingly, 17 exhibited stronger direct SIRT1 activative ability and induced higher SIRT1 expression capability compared to the lead. Furthermore, 17 attenuates oxidative stress-induced cardiomyocytes apoptosis by activating the SIRT1-PGC1α signaling pathway. Our study validated the promising potential of activating SIRT1 and promoting SIRT1 expression through H2 S to improve cardiomyocytes function, providing novel insights into the protective mechanisms during the progression of ischemic heart disease.- Published
- 2024
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