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.