GYY4137 protects against type 2 diabetes mellitus-associated myocardial autophagy by suppressing FOXO1 signal pathway

<b>Purpose:</b> Diabetic cardiomyopathy (DCM) is a major complication of type 2 diabetes mellitus (T2DM), but its effective prevention and treatment are still limited. We investigated the effects of GYY4137, a slow-releasing hydrogen sulfide donor, and its downstream mediator forkhead box protein O1 (FOXO1) on T2DM-associated DCM. <b>Methods:</b> <i>In vivo</i>, T2DM mice were induced by a high-fat diet coupled with streptozotocin injection. Intragastric administration of GYY4137 was also performed. <i>In vitro</i>, AC16 cardiomyocytes were treated with glucose and palmitate to mimic high-glucose and high-fat (HGHF) conditions, in which GYY4137 or a FOXO1 inhibitor (AS1842856) was also introduced. Bioinformatics analysis was performed using public GEO datasets. <b>Results</b>: GYY4137 demonstrated a protective effect against cardiac dysfunction, fibrosis, and autophagy in cardiac tissues of T2DM mice. Moreover, GYY4137 alleviated cell injury and lipid accumulation in HGHF-treated AC16 cells. In both <i>in vivo</i> and <i>in vitro</i> models, hyperactivation of autophagy was dampened by GYY4137. Bioinformatic analysis revealed the potential role of the FOXO pathway and autophagy in DCM. Further experiments showed that GYY4137 rescued diabetes-induced overexpression of FOXO1. AS1842856 displayed a notable capacity to shield cardiomyocytes against diabetes-induced injury similar to that achieved by GYY4137. <b>Conclusion:</b> GYY4137 protected against cardiac dysfunction and fibrosis in T2DM mice, and the mechanism might involve suppression of FOXO1-induced autophagy.