Exogenous Hydrogen Sulfide Attenuates The Development Of Diabetic Cardiomyopathy Via The FoxO1 Pathway

Background:Previous studies have suggested that exogenous hydrogen sulfide can alleviate the development of diabetic cardiomyopathy?DCM?by inhibiting oxidative stress,inflammation,and apoptosis.However,the underlying mechanism is not fully understood.Nuclear expression and function of the transcription factor Forkhead box protein O?FoxO1?have been associated with cardiovascular diseases,and thus,the importance of FoxO1 in DCM has gained increasing attention.This study was designed to investigate the interactions between H₂S and nuclear FoxO1 in DCM.Accumulating evidence suggests that the concentration of H₂S is lower in patients with DM and rats with streptozotocin?STZ?-induced diabetes.H₂S has been shown to be a robust cardioprotective agent in various animal models,including ischemia/reperfusion injury and DCM models,that neutralizes reactive oxygen species?ROS?,reduces apoptotic signaling,modulates mitochondrial respiration,and decreases inflammation.Methods:Diabetes was induced in adult male C57BL/6J mice by intraperitoneal injection of streptozotocin and was treated with H₂S donor sodium hydrosulfide?NaHS?for 12 weeks.The H9C2 cardiomyoblast cell line and neonatal rat cardiomyocytes?NRCMs?were treated with the slow-releasing H₂S donor GYY4137prior to high glucose?HG?exposure with or without pretreatment with the Akt inhibitor MK-2206 2HCl.Changes in FoxO1 protein phosphorylation and subcellular localization were determined in H9C2 cells,NRCMs,and cardiac tissues from normal and diabetic mice.Cardiac structure and function in the diabetic mice were evaluated by echocardiography and histological analysis and compared with those in control animals.Results:The echocardiographic and histopathological data indicated that exogenous H₂S improved cardiac function and attenuated cardiac hypertrophy and myocardial fibrosis in diabetic mice.H₂S also improved HG-induced oxidative stress and apoptosis in cardiac tissue and NRCMs.In addition,H₂S induced FoxO1phosphorylation and nuclear exclusion in vitro and in vivo,and this function was not inhibited by MK-2206 2HCl.Alanine substitution mutation of three sites in FoxO1enhanced FoxO1 transcriptional activity,and subsequent treatment with exogenous H₂S could not prevent HG-induced nuclear retention.Conclusion:Our data indicate that H₂S is a novel regulator of FoxO1 in cardiac cells and provide evidence supporting the potential of H₂S in inhibiting the progression of DCM.