Curcumin reduces myocardial ischemia-reperfusion injury, by increasing endogenous H2S levels and further modulating m6A

Background Our previous research shows that Curcumin (CUR) attenuates myocardial ischemia-reperfusion injury (MIRI) by reducing intracellular total RNA m(6)A levels. However, the mechanism remains unknown. Methods For ischemia-reperfusion (IR), H9c2 cells were cultured for 6 h in serum-free low-glycemic (1 g/L) medium and a gas environment without oxygen, and then cultured for 6 h in high-glycemic (4.5 g/L) medium supplemented with 10% FBS and a 21% oxygen environment. The effects of different concentrations of CUR (5, 10, and 20 mu M) treatments on signaling molecules in conventionally cultured and IR-treated H9c2 cells were examined. Results CUR treatment significantly up-regulated the H2S levels, and the mRNA and protein expression of cystathionine gamma-lyase (CSE), and down-regulated the mRNAs and proteins levels of thiosulfate sulfurtransferase (TST) and ethylmalonic encephalopathy 1 (ETHE1) in H9c2 cells conventionally cultured and subjected to IR. Exogenous H2S supply (NaHS and GYY4137) significantly reduced intracellular total RNA m(6)A levels, and the expression of RNA m(6)A "writers" METTL3 and METTL14, and increased the expression of RNA m(6)A "eraser" FTO in H9c2 cells conventionally cultured and subjected to IR. CSE knockdown counteracted the inhibitory effect of CUR treatment on ROS production, promotion on cell viability, and inhibition on apoptosis of H9c2 cells subjected to IR. Conclusion CUR attenuates MIRI by regulating the expression of H2S level-regulating enzymes and increasing the endogenous H2S levels. Increased H2S levels could regulate the m(6)A-related proteins expression and intracellular total RNA m(6)A levels.