Discovery of SIRT1-Activating Hydrogen Sulfide Donating Derivatives for Efficient Resistant of Myocardial Ischemic Injury

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 H2S donating
derivatives were designed and synthesized. Among them, compound 17 exerted an effective cardioprotective effect in
vitro and in vivo. The addition of H2S scavenger attenuated the protective activity, emphasizing
the critical involvement of H2S 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 H2S to improve cardiomyocytes function, providing novel insights into
the protective mechanisms during the progression of ischemic heart
disease.