Hydrogen sulfide protects cardiomyocytes against apoptosis in ischemia/reperfusion through MiR-1-regulated histone deacetylase 4 pathway

Abstract

Background/Aims: Hydrogen sulfide (H 2 S) is a powerful inhibitor of cardiomyocytes apoptosis following ischemia/reperfusion (IR) injury, but the underlying mechanism remains unclear. Our previous study showed that microRNA-1 (miR-1) was upregulated by 2.21 fold in the IR group compared with that in the H 2 S preconditioned group. MiR-206 affected the process of cardiomyocytes hypertrophy by regulating histone deacetylase 4 (HDAC4). HDAC4 is also known to play an anti-apoptotic role in tumor cells, but its role in the myocardium has not been reported. The aim of this study was to test whether H 2 S could inhibit apoptosis of cardiomyocytes through HDAC4 regulation by miR-1 in IR. Methods: Cardiomyocytes of neonatal rats were subjected to hypoxia/reoxygenation (HR) injury with or without H 2 S pretreatment to simulate IR injury. Cardiomyocytes were transfected with miR-1 mimic or HDAC4 siRNA to evaluate whether the miR-1-HDAC4 signaling pathway was involved in the protective effect of H 2 S. Results: HR increased cell apoptosis and caspase-3 cleavage, upregulated miR-1, and downregulated HDAC4. H 2 S preconditioning attenuated the apoptosis of cardiomyocytes, caspase-3 cleavage and LDH release, and enhanced cell viability. In addition, H 2 S downregulated miR-1, and preserved HDAC4 expression. HDAC4 protein was down-regulated by miR-1 mimic. Transfection of cardiomyocytes with miR-1 mimic partially reduced the protective effect of H 2 S. Meanwhile, transfection of cardiomyocytes with siRNA to HDAC4 partially abrogated the protective effect of H 2 S. Conclusions: The miR-1-HDAC4 signaling pathway is involved in the protective effect of H 2 S against the apoptosis of cardiomyocytes during the IR injury process.