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Exogenous hydrogen sulfide attenuates the development of diabetic cardiomyopathy via the FoxO1 pathway
Author(s) -
Ye Peng,
Gu Yue,
Zhu YanRong,
Chao YueLin,
Kong XiangQuan,
Luo Jie,
Ren XiaoMin,
Zuo GuangFeng,
Zhang DaiMin,
Chen ShaoLiang
Publication year - 2018
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26946
Subject(s) - diabetic cardiomyopathy , foxo1 , streptozotocin , oxidative stress , medicine , cardiac function curve , endocrinology , protein kinase b , diabetes mellitus , apoptosis , chemistry , cardiomyopathy , heart failure , biochemistry
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 hydrogen sulfide (H 2 S) and nuclear FoxO1 in DCM. Methods Diabetes was induced in adult male C57BL/6J mice by intraperitoneal injection of streptozotocin and was treated with H 2 S donor sodium hydrosulfide for 12 weeks. The H9C2 cardiomyoblast cell line and neonatal rat cardiomyocytes (NRCMs) were treated with the slow‐releasing H 2 S donor GYY4137 before 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 H 2 S improved cardiac function and attenuated cardiac hypertrophy and myocardial fibrosis in diabetic mice. H 2 S also improved HG‐induced oxidative stress and apoptosis in cardiac tissue and NRCMs. In addition, H 2 S induced FoxO1 phosphorylation 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 FoxO1‐enhanced FoxO1 transcriptional activity, and subsequent treatment with exogenous H 2 S could not prevent HG‐induced nuclear retention. Conclusions Our data indicate that H 2 S is a novel regulator of FoxO1 in cardiac cells and provide evidence supporting the potential of H 2 S in inhibiting the progression of DCM.