The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Gaseous signal molecule SO2 regulates autophagy through PI3K/AKT pathway inhibits cardiomyocyte apoptosis and improves myocardial fibrosis in rats with type II diabetes

  • Zhao, Junxiong (Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China) ;
  • Wu, Qian (Department of General Practice, The Second Affiliated Hospital, Hengyang Medical School, University of South China) ;
  • Yang, Ting (Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China) ;
  • Nie, Liangui (Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China) ;
  • Liu, Shengquan (Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China) ;
  • Zhou, Jia (Department of Ultrasound Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China) ;
  • Chen, Jian (Department of Critical Care Medicine, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China) ;
  • Jiang, Zhentao (Department of Cardiology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China) ;
  • Xiao, Ting (Department of Cardiology, Shenzhen Longhua District Central Hospital, Longhua Central Hospital Affiliated Guang-dong Medical University) ;
  • Yang, Jun (Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China) ;
  • Chu, Chun (Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China)
  • Received : 2022.07.29
  • Accepted : 2022.09.13
  • Published : 2022.11.01
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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

Acknowledgement

This project was supported by the National Natural Science Foundation of China (No. 81870230 and No.82074236), Clinical Major Projects of Hunan Provincial Health Commission (No. 20201913), the Natural Science Foundation of Hunan Province (No.2021JJ70035, No. 2021JJ40499 and No. 2021JJ70116), and Longhua district - level research projects of Shenzhen (No. 2020035).

References

  1. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, Colagiuri S, Guariguata L, Motala AA, Ogurtsova K, Shaw JE, Bright D, Williams R. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843. https://doi.org/10.1016/j.diabres.2019.107843
  2. Horton WB, Barrett EJ. Microvascular dysfunction in diabetes mellitus and cardiometabolic disease. Endocr Rev. 2021;42:29-55. https://doi.org/10.1210/endrev/bnaa025
  3. Dall TM, Yang W, Gillespie K, Mocarski M, Byrne E, Cintina I, Beronja K, Semilla AP, Iacobucci W, Hogan PF. The economic burden of elevated blood glucose levels in 2017: diagnosed and undiagnosed diabetes, gestational diabetes mellitus, and prediabetes. Diabetes Care. 2019;42:1661-1668. https://doi.org/10.2337/dc18-1226
  4. Lam HCY, Chan JCN, Luk AOY, Chan EYY, Goggins WB. Shortterm association between ambient temperature and acute myocardial infarction hospitalizations for diabetes mellitus patients: a time series study. PLoS Med. 2018;15:e1002612. https://doi.org/10.1371/journal.pmed.1002612
  5. Seferovic PM, Polovina M, Bauersachs J, Arad M, Ben Gal T, Lund LH, Felix SB, Arbustini E, Caforio ALP, Farmakis D, Filippatos GS, Gialafos E, Kanjuh V, Krljanac G, Limongelli G, Linhart A, Lyon AR, Maksimovic R, Milicic D, Milinkovic I, et al. Heart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2019;21:553-576. https://doi.org/10.1002/ejhf.1461
  6. Tromp J, Lim SL, Tay WT, Teng TK, Chandramouli C, Ouwerkerk W, Wander GS, Sawhney JPS, Yap J, MacDonald MR, Ling LH, Sattar N, McMurray JJV, Richards AM, Anand I, Lam CSP. Microvascular disease in patients with diabetes with heart failure and reduced ejection versus preserved ejection fraction. Diabetes Care. 2019;42:1792-1799. https://doi.org/10.2337/dc18-2515
  7. Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ Res. 2018;122:624-638. https://doi.org/10.1161/CIRCRESAHA.117.311586
  8. Kenny HC, Abel ED. Heart failure in type 2 diabetes mellitus. Circ Res. 2019;124:121-141. https://doi.org/10.1161/CIRCRESAHA.118.311371
  9. Seferovic PM, Petrie MC, Filippatos GS, Anker SD, Rosano G, Bauersachs J, Paulus WJ, Komajda M, Cosentino F, de Boer RA, Farmakis D, Doehner W, Lambrinou E, Lopatin Y, Piepoli MF, Theodorakis MJ, Wiggers H, Lekakis J, Mebazaa A, Mamas MA, et al. Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2018;20:853-872. https://doi.org/10.1002/ejhf.1170
  10. Liu M, Lopez de Juan Abad B, Cheng K. Cardiac fibrosis: myofibroblast-mediated pathological regulation and drug delivery strategies. Adv Drug Deliv Rev. 2021;173:504-519. https://doi.org/10.1016/j.addr.2021.03.021
  11. Miki T, Yuda S, Kouzu H, Miura T. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail Rev. 2013;18:149-166. https://doi.org/10.1007/s10741-012-9313-3
  12. Ma T, Huang X, Zheng H, Huang G, Li W, Liu X, Liang J, Cao Y, Hu Y, Huang Y. SFRP2 improves mitochondrial dynamics and mitochondrial biogenesis, oxidative stress, and apoptosis in diabetic cardiomyopathy. Oxid Med Cell Longev. 2021;2021:9265016.
  13. Yu W, Zha W, Ren J. Exendin-4 and liraglutide attenuate glucose toxicity-induced cardiac injury through mTOR/ULK1-dependent autophagy. Oxid Med Cell Longev. 2018;2018:5396806.
  14. Lusha E, Jiang H. Simvastatin protects high glucose-induced H9c2 cells from injury by inducing autophagy. Pharm Biol. 2020;58:1077-1084.
  15. Dewanjee S, Vallamkondu J, Kalra RS, John A, Reddy PH, Kandimalla R. Autophagy in the diabetic heart: a potential pharmacotherapeutic target in diabetic cardiomyopathy. Ageing Res Rev. 2021;68:101338. https://doi.org/10.1016/j.arr.2021.101338
  16. Li Y, Liu M, Song X, Zheng X, Yi J, Liu D, Wang S, Chu C, Yang J. Exogenous hydrogen sulfide ameliorates diabetic myocardial fibrosis by inhibiting cell aging through SIRT6/AMPK autophagy. Front Pharmacol. 2020;11:1150. https://doi.org/10.3389/fphar.2020.01150
  17. Yao Q, Ke ZQ, Guo S, Yang XS, Zhang FX, Liu XF, Chen X, Chen HG, Ke HY, Liu C. Curcumin protects against diabetic cardiomyopathy by promoting autophagy and alleviating apoptosis. J Mol Cell Cardiol. 2018;124:26-34. https://doi.org/10.1016/j.yjmcc.2018.10.004
  18. Tewari D, Patni P, Bishayee A, Sah AN, Bishayee A. Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: a novel therapeutic strategy. Semin Cancer Biol. 2022:80:1-17. https://doi.org/10.1016/j.semcancer.2019.12.008
  19. Chen E, Chen C, Niu Z, Gan L, Wang Q, Li M, Cai X, Gao R, Katakam S, Chen H, Zhang S, Zhou R, Cheng X, Qiu Y, Yu H, Zhu T, Liu J. Poly(I:C) preconditioning protects the heart against myocardial ischemia/reperfusion injury through TLR3/PI3K/Aktdependent pathway. Signal Transduct Target Ther. 2020;5:216. https://doi.org/10.1038/s41392-020-00257-w
  20. Ke X, Hao Y, Li B, Zou J, Li X, Wei C, Liu F, Zhang Z. Vaspin prevents tumor necrosis factor-α-induced apoptosis in cardiomyocytes by promoting autophagy. J Cardiovasc Pharmacol. 2018;77:257-267. https://doi.org/10.1097/FJC.0000000000000562
  21. Jia M, Qiu H, Lin L, Zhang S, Li D, Jin D. Inhibition of PI3K/AKT/mTOR signalling pathway activates autophagy and suppresses peritoneal fibrosis in the process of peritoneal dialysis. Front Physiol. 2022;13:778479. https://doi.org/10.3389/fphys.2022.778479
  22. Lei L, Zhao J, Liu XQ, Chen J, Qi XM, Xia LL, Wu YG. Wogonin alleviates kidney tubular epithelial injury in diabetic nephropathy by inhibiting PI3K/Akt/NF-κB signaling pathways. Drug Des Devel Ther. 2021;15:3131-3150. https://doi.org/10.2147/DDDT.S310882
  23. Wang K, Li Z, Sun Y, Liu X, Ma W, Ding Y, Hong J, Qian L, Xu D. Dapagliflozin improves cardiac function, remodeling, myocardial apoptosis, and inflammatory cytokines in mice with myocardial infarction. J Cardiovasc Transl Res. 2021. doi:10.1007/s12265-021-10192-y
  24. Yang X, Li X, Lin Q, Xu Q. Up-regulation of microRNA-203 inhibits myocardial fibrosis and oxidative stress in mice with diabetic cardiomyopathy through the inhibition of PI3K/Akt signaling pathway via PIK3CA. Gene. 2019;715:143995. https://doi.org/10.1016/j.gene.2019.143995
  25. Huang Y, Zhang H, Lv B, Tang C, Du J, Jin H. Sulfur dioxide: endogenous generation, biological effects, detection, and therapeutic potential. Antioxid Redox Signal. 2022;36:256-274. https://doi.org/10.1089/ars.2021.0213
  26. Liu M, Liu S, Tan W, Tang F, Long J, Li Z, Liang B, Chu C, Yang J. Gaseous signalling molecule SO2 via Hippo-MST pathway to improve myocardial fibrosis of diabetic rats. Mol Med Rep. 2017;16:8953-8963. https://doi.org/10.3892/mmr.2017.7714
  27. Zhang LL, Du JB, Tang CS, Jin HF, Huang YQ. Inhibitory effects of sulfur dioxide on rat myocardial fibroblast proliferation and migration. Chin Med J (Engl). 2018;131:1715-1723. https://doi.org/10.4103/0366-6999.235875
  28. Wang JW, Ye XY, Wei N, Wu SS, Zhang ZH, Luo GH, Li X, Li J, Cao H. Reactive oxygen species contributes to type 2 diabetic neuropathic pain via the thioredoxin-interacting protein-NOD-like receptor protein 3- N -methyl-D-aspartic acid receptor 2B pathway. Anesth Analg. 2022;135:865-876. https://doi.org/10.1213/ANE.0000000000006117
  29. Yang L, Zhang H, Chen P. Sulfur dioxide attenuates sepsis-induced cardiac dysfunction via inhibition of NLRP3 inflammasome activation in rats. Nitric Oxide. 2018;81:11-20. https://doi.org/10.1016/j.niox.2018.09.005
  30. Li Z, Huang Y, Du J, Liu AD, Tang C, Qi Y, Jin H. Endogenous sulfur dioxide inhibits vascular calcification in association with the TGF-β/Smad signaling pathway. Int J Mol Sci. 2016;17:266. https://doi.org/10.3390/ijms17030266
  31. Zhang D, Wang X, Tian X, Zhang L, Yang G, Tao Y, Liang C, Li K, Yu X, Tang X, Tang C, Zhou J, Kong W, Du J, Huang Y, Jin H. The increased endogenous sulfur dioxide acts as a compensatory mechanism for the downregulated endogenous hydrogen sulfide pathway in the endothelial cell inflammation. Front Immunol. 2018;9:882. https://doi.org/10.3389/fimmu.2018.00882
  32. Han D, Rozanski A, Gransar H, Sharir T, Einstein AJ, Fish MB, Ruddy TD, Kaufmann PA, Sinusas AJ, Miller EJ, Bateman TM, Dorbala S, Di Carli M, Liang JX, Hu LH, Germano G, Dey D, Berman DS, Slomka PJ. Myocardial ischemic burden and differences in prognosis among patients with and without diabetes: results from the multicenter international REFINE SPECT registry. Diabetes Care. 2020;43:453-459. https://doi.org/10.2337/dc19-1360
  33. Shin SH, Claggett B, Pfeffer MA, Skali H, Liu J, Aguilar D, Diaz R, Dickstein K, Gerstein HC, Kober LV, Lawson FC, Lewis EF, Maggioni AP, McMurray JJV, Probstfield JL, Riddle MC, Tardif JC, Solomon SD. Hyperglycaemia, ejection fraction and the risk of heart failure or cardiovascular death in patients with type 2 diabetes and a recent acute coronary syndrome. Eur J Heart Fail. 2020;22:1133-1143. https://doi.org/10.1002/ejhf.1790
  34. Wamil M, Coleman RL, Adler AI, McMurray JJV, Holman RR. Increased risk of incident heart failure and death is associated with insulin resistance in people with newly diagnosed type 2 diabetes: UKPDS 89. Diabetes Care. 2021;44:1877-1884. https://doi.org/10.2337/dc21-0429
  35. Sacre JW, Magliano DJ, Shaw JE. Incidence of hospitalization for heart failure relative to major atherosclerotic events in type 2 diabetes: a meta-analysis of cardiovascular outcomes trials. Diabetes Care. 2020;43:2614-2623. https://doi.org/10.2337/dc20-0654
  36. Paulus WJ, Dal Canto E. Distinct myocardial targets for diabetes therapy in heart failure with preserved or reduced ejection fraction. JACC Heart Fail. 2018;6:1-7. https://doi.org/10.1016/j.jchf.2017.07.012
  37. Faria A, Persaud SJ. Cardiac oxidative stress in diabetes: mechanisms and therapeutic potential. Pharmacol Ther. 2017;172:50-62. https://doi.org/10.1016/j.pharmthera.2016.11.013
  38. Guido MC, Marques AF, Tavares ER, Tavares de Melo MD, Salemi VMC, Maranhao RC. The effects of diabetes induction on the rat heart: differences in oxidative stress, inflammatory cells, and fibrosis between subendocardial and interstitial myocardial areas. Oxid Med Cell Longev. 2017;2017:5343972.
  39. Li L, Zhao Q, Kong W. Extracellular matrix remodeling and cardiac fibrosis. Matrix Biol. 2018;68-69:490-506. https://doi.org/10.1016/j.matbio.2018.01.013
  40. Tuleta I, Frangogiannis NG. Fibrosis of the diabetic heart: clinical significance, molecular mechanisms, and therapeutic opportunities. Adv Drug Deliv Rev. 2021;176:113904. https://doi.org/10.1016/j.addr.2021.113904
  41. Wang CY, Li XD, Hao ZH, Xu D. Insulin-like growth factor-1 improves diabetic cardiomyopathy through antioxidative and antiinflammatory processes along with modulation of Akt/GSK-3β signaling in rats. Korean J Physiol Pharmacol. 2016;20:613-619. https://doi.org/10.4196/kjpp.2016.20.6.613
  42. Chiang MH, Liang CJ, Lin LC, Yang YF, Huang CC, Chen YH, Kao HL, Chen YC, Ke SR, Lee CW, Lin MS, Chen YL. miR-26a attenuates cardiac apoptosis and fibrosis by targeting ataxia-telangiectasia mutated in myocardial infarction. J Cell Physiol. 2020;235:6085-6102. https://doi.org/10.1002/jcp.29537
  43. Li J, Salvador AM, Li G, Valkov N, Ziegler O, Yeri A, Yang Xiao C, Meechoovet B, Alsop E, Rodosthenous RS, Kundu P, Huan T, Levy D, Tigges J, Pico AR, Ghiran I, Silverman MG, Meng X, Kitchen R, Xu J, et al. Mir-30d regulates cardiac remodeling by intracellular and paracrine signaling. Circ Res. 2021;128:e1-e23.
  44. Zou MH, Xie Z. Regulation of interplay between autophagy and apoptosis in the diabetic heart: new role of AMPK. Autophagy. 2013;9:624-625. https://doi.org/10.4161/auto.23577
  45. Das CK, Banerjee I, Mandal M. Pro-survival autophagy: an emerging candidate of tumor progression through maintaining hallmarks of cancer. Semin Cancer Biol. 2020;66:59-74. https://doi.org/10.1016/j.semcancer.2019.08.020
  46. Sciarretta S, Maejima Y, Zablocki D, Sadoshima J. The role of autophagy in the heart. Annu Rev Physiol. 2018;80:1-26. https://doi.org/10.1146/annurev-physiol-021317-121427
  47. Zhang M, Sui W, Xing Y, Cheng J, Cheng C, Xue F, Zhang J, Wang X, Zhang C, Hao P, Zhang Y. Angiotensin IV attenuates diabetic cardiomyopathy via suppressing FoxO1-induced excessive autophagy, apoptosis and fibrosis. Theranostics. 2021;11:8624-8639. https://doi.org/10.7150/thno.48561
  48. Liu BY, Li L, Liu GL, Ding W, Chang WG, Xu T, Ji XY, Zheng XX, Zhang J, Wang JX. Baicalein attenuates cardiac hypertrophy in mice via suppressing oxidative stress and activating autophagy in cardiomyocytes. Acta Pharmacol Sin. 2021;42:701-714. https://doi.org/10.1038/s41401-020-0496-1
  49. Li X, Ke X, Li Z, Li B. Vaspin prevents myocardial injury in rats model of diabetic cardiomyopathy by enhancing autophagy and inhibiting inflammation. Biochem Biophys Res Commun. 2019;514:1-8. https://doi.org/10.1016/j.bbrc.2019.04.110
  50. Wu MX, Wang SH, Xie Y, Chen ZT, Guo Q, Yuan WL, Guan C, Xu CZ, Huang YN, Wang JF, Zhang HF, Chen YX. Interleukin-33 alleviates diabetic cardiomyopathy through regulation of endoplasmic reticulum stress and autophagy via insulin-like growth factorbinding protein 3. J Cell Physiol. 2021;236:4403-4419. https://doi.org/10.1002/jcp.30158
  51. Magaye RR, Savira F, Hua Y, Xiong X, Huang L, Reid C, Flynn BL, Kaye D, Liew D, Wang BH. Attenuating PI3K/Akt- mTOR pathway reduces dihydrosphingosine 1 phosphate mediated collagen synthesis and hypertrophy in primary cardiac cells. Int J Biochem Cell Biol. 2021;134:105952. https://doi.org/10.1016/j.biocel.2021.105952
  52. Han Y, Cai X, Pan M, Gong J, Cai W, Lu D, Xu C. MicroRNA-21-5p acts via the PTEN/Akt/FOXO3a signaling pathway to prevent cardiomyocyte injury caused by high glucose/high fat conditions. Exp Ther Med. 2022;23:230. https://doi.org/10.3892/etm.2022.11154
  53. Wang XB, Huang XM, Ochs T, Li XY, Jin HF, Tang CS, Du JB. Effect of sulfur dioxide preconditioning on rat myocardial ischemia/ reperfusion injury by inducing endoplasmic reticulum stress. Basic Res Cardiol. 2011;106:865-878. https://doi.org/10.1007/s00395-011-0176-x
  54. Li Y, Feng Y, Ye X, Peng H, Du J, Yao X, Huang Y, Jin H, Du J. Endogenous SO2 controls cell apoptosis: the state-of-the-art. Front Cell Dev Biol. 2021;9:729728. https://doi.org/10.3389/fcell.2021.729728
  55. Chen Q, Zhang L, Chen S, Huang Y, Li K, Yu X, Wu H, Tian X, Zhang C, Tang C, Du J, Jin H. Downregulated endogenous sulfur dioxide/aspartate aminotransferase pathway is involved in angiotensin II-stimulated cardiomyocyte autophagy and myocardial hypertrophy in mice. Int J Cardiol. 2016;225:392-401. https://doi.org/10.1016/j.ijcard.2016.09.111
  56. Liang Y, Liu D, Ochs T, Tang C, Chen S, Zhang S, Geng B, Jin H, Du J. Endogenous sulfur dioxide protects against isoproterenol-induced myocardial injury and increases myocardial antioxidant capacity in rats. Lab Invest. 2011;91:12-23. https://doi.org/10.1038/labinvest.2010.156
  57. Wang XB, Cui H, Du JB. Sulfur dioxide ameliorates rat myocardial fibrosis by inhibiting endoplasmic reticulum stress. Histol Histopathol. 2018;33:1089-1097.