Hydrogen sulfide (H₂S) attenuates lipotoxicity and cardiac cell senescence by regulating protein acetylation

Abstract

Hydrogen sulfide (H2S) is recently recognized as a novel gasotransmitter. H2S can be endogenously generated from cysteine in mammalian tissues, and cystathionine gamma-lyase (CSE) is a critical enzyme generating H2S in the cardiovascular system. Increasing evidence suggests that interference in H2S production is related to heart diseases. Obesity is a leading risk factor for heart dysfunctions by interrupting lipid metabolism. In the current work, the regulatory roles of the CSE/H2S system on lipid overload-induced lipotoxicity and cardiac senescence were explored. Here, it was found that incubation of H9C2 rat cardiomyocyte cells with a lipid mixture inhibited cell viability and promoted the cellular accumulation of lipids, formation of reactive oxygen species, mitochondrial dysfunctions, and lipid peroxidation; all of these could be reversed through incubation with the exogenously applied NaHS (the H2S donor). Further data revealed that H2S protected H9C2 cells from lipid overload-induced senescence by altering the expression of genes related to lipid metabolism and inhibiting both the production of acetyl-CoA and the level of protein acetylation. In vivo, knockout of the CSE gene strengthened cardiac lipid accumulation, protein acetylation, and cellular ageing in the mice fed a high-fat diet. Taken together, the CSE/H2S system is essential for maintaining lipid homeostasis and cellular senescence in heart cells under lipid overload. The CSE/H2S system would serve as a target for preventing and treating obesity and age-related heart diseases.