Protective role of hydrogen sulfide against diabetic cardiomyopathy via alleviating necroptosis

Diabetic cardiomyopathy lacks effective and novel methods. Hydrogen sulfide (H2S) as the third gasotransmitter plays an important role in the cardiovascular system. Our study was to elucidate the protective effect and possible mechanism of H2S on diabetic cardiomyopathy from the perspective of necroptosis. Leptin receptor deficiency (db/db) mice and streptozotocin (STZ)-induced diabetic cystathionine-γ-lyase (CSE) knockout (KO) mice were investigated. In addition, cardiomyocytes were stimulated with high glucose. We found that plasma H2S level, myocardial H2S production and CSE mRNA expression was impaired in the diabetic mice. CSE deficiency exacerbated diabetic cardiomyopathy, and promoted myocardial oxidative stress, necroptosis and inflammasome in STZ-induced mice. CSE inhibitor dl-propargylglycine (PAG) aggravated cell damage and oxidative stress, deteriorated necroptosis and inflammasome in cardiomyocytes with high glucose stimulation. H2S donor sodium hydrosulfide (NaHS) improved diabetic cardiomyopathy, attenuated myocardial oxidative stress, necroptosis and the NLR family pyrin domain-containing protein 3 (NLRP3) in db/db mice. NaHS also alleviated cell damage, oxidative stress, necroptosis and inflammasome in cardiomyocytes with high glucose stimulation. In Conclusion, H2S deficiency aggravated mitochondrial damage, increased reactive oxygen species accumulation, promoted necroptosis, activated NLRP3 inflammasome, and finally exacerbated diabetic cardiomyopathy. Exogenous H2S supplementation alleviated necroptosis to suppress NLRP3 inflammasome activation and attenuate diabetic cardiomyopathy via mitochondrial dysfunction improvement and oxidative stress inhibition. Our study provides the first evidence and a new mechanism that necroptosis inhibition by a pharmacological manner of H2S administration protected against diabetic cardiomyopathy. It is beneficial to provide a novel strategy for the prevention and treatment of diabetic cardiomyopathy.