Gaseous signal molecule SO2 regulates autophagy through PI3K/AKT pathway inhibits cardiomyocyte apoptosis and improves myocardial fibrosis in rats with type II diabetes

Junxiong Zhao; Qian Wu; Ting Yang; Liangui Nie; Shengquan Liu; Jia Zhou; Jian Chen; Zhentao Jiang; Ting Xiao; Jun Yang; Chun Chu

doi:10.4196/kjpp.2022.26.6.541

Gaseous signal molecule SO₂ regulates autophagy through PI3K/AKT pathway inhibits cardiomyocyte apoptosis and improves myocardial fibrosis in rats with type II diabetes

Korean J Physiol Pharmacol. 2022 Nov 1;26(6):541-556. doi: 10.4196/kjpp.2022.26.6.541.

Authors

Junxiong Zhao^{1

2}, Qian Wu³, Ting Yang^{1

4}, Liangui Nie², Shengquan Liu², Jia Zhou⁵, Jian Chen⁶, Zhentao Jiang⁷, Ting Xiao⁸, Jun Yang², Chun Chu¹

Affiliations

¹ Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China.
² Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China.
³ Department of General Practice, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China.
⁴ School of Pharmaceutical Science of University of South China, Hengyang 421000, China.
⁵ Department of Ultrasound Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China.
⁶ Department of Critical Care Medicine, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China.
⁷ Department of Cardiology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China.
⁸ Department of Cardiology, Shenzhen Longhua District Central Hospital, Longhua Central Hospital Affiliated Guang-dong Medical University, Shenzhen 518000, China.

Abstract

Myocardial fibrosis is a key link in the occurrence and development of diabetic cardiomyopathy. Its etiology is complex, and the effect of drugs is not good. Cardiomyocyte apoptosis is an important cause of myocardial fibrosis. The purpose of this study was to investigate the effect of gaseous signal molecule sulfur dioxide (SO₂) on diabetic myocardial fibrosis and its internal regulatory mechanism. Masson and TUNEL staining, Western-blot, transmission electron microscopy, RT-qPCR, immunofluorescence staining, and flow cytometry were used in the study, and the interstitial collagen deposition, autophagy, apoptosis, and changes in phosphatidylinositol 3-kinase (PI3K)/AKT pathways were evaluated from in vivo and in vitro experiments. The results showed that diabetic myocardial fibrosis was accompanied by cardiomyocyte apoptosis and down-regulation of endogenous SO₂-producing enzyme aspartate aminotransferase (AAT)_1/2. However, exogenous SO₂ donors could up-regulate AAT1/2, reduce apoptosis of cardiomyocytes induced by diabetic rats or high glucose, inhibit phosphorylation of PI3K/AKT protein, up-regulate autophagy, and reduce interstitial collagen deposition. In conclusion, the results of this study suggest that the gaseous signal molecule SO₂ can inhibit the PI3K/AKT pathway to promote cytoprotective autophagy and inhibit cardiomyocyte apoptosis to improve myocardial fibrosis in diabetic rats. The results of this study are expected to provide new targets and intervention strategies for the prevention and treatment of diabetic cardiomyopathy.

Keywords: Apoptosis; Autophagy; Myocardial fibrosis; PI3K/AKT pathway; Sulfur dioxide.