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Mechanism of Hydrogen Sulfide Preconditioning-Associated Protection Against Ischemia–Reperfusion Injury Differs in Diabetic Heart That Develops Myopathy

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Abstract

Hydrogen sulfide (H2S) is reported to be effective in the management of the myocardial ischemia–reperfusion (I/R) injury via PI3K/GSK3β pathway in normal rats. However, its efficacy against I/R in the presence of diabetic cardiomyopathy is relatively obscure. Thus, the present work aimed to find out H2S-mediated cardioprotection against I/R in diabetic cardiomyopathy and to evaluate its mode of action using Langendorff isolated heart perfusion system. The present work includes three groups of rat, viz. (i) normal, (ii) diabetes mellitus (DM: streptozotocin: 35 mg/kg; normal diet), and (iii) diabetes + high-fat diet (DCM) (streptozotocin: 35 mg/kg; high-fat diet). The effect of NaHS (an H2S donor; 20 µM) on cardiac function in isolated rat hearts demonstrates that H2S preconditioning (HIPC) significantly attenuated myocardial injury in both DM and DCM hearts, as evidenced by the (i) improvement in hemodynamics, which includes rate pressure product [(in mmHg × 103 × bpm) DM: 40 to 56; DCM: 21 to 58] and left ventricular developed pressure [(in mmHg) DM: 53 to 74; DCM: 28 to 74), (ii) reduction in infarct size (25% to 8%) and attenuated caspase activity, compared to their respective I/R controls. Also, the observed positive recovery of mitochondrial function during HIPC treatment reinforces the cardioprotection by HIPC in DCM heart against I/R injury. However, HIPC could not repair I/R-induced oxidative stress in DCM rat heart. Further, to study the H2S mode of action, the experimental rats were exposed to a PI3K inhibitor (Wortmannin) and GSK3β inhibitor (SB216763) before HIPC protocol, whose results suggest that unlike in normal and DM, HIPC mediates its cardioprotective effect independent of PI3K/GSK3β pathway. To conclude, HIPC ameliorates I/R injury in DCM rat via an alternative pathway other than existing PI3K pathway, which is required to be probed under disease conditions.

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References

  1. Hausenloy, D. J., & Yellon, D. M. (2013). Myocardial ischemia-reperfusion injury: A neglected therapeutic target. Journal of Clinical Investigation,123(1), 92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Heusch, G., Boengler, K., & Schulz, R. (2010). Inhibition of mitochondrial permeability transition pore opening: The Holy Grail of cardioprotection. Basic Research in Cardiology,105(2), 151–154.

    Article  PubMed  Google Scholar 

  3. Grundy, S. M., Benjamin, I. J., Burke, G. L., Chait, A., Eckel, R. H., Howard, B. V., et al. (1999). Diabetes and cardiovascular disease: A statement for health professionals from the American Heart Association. Circulation,100(10), 1134–1146.

    Article  CAS  PubMed  Google Scholar 

  4. Vinik, A. I., Erbas, T., & Casellini, C. M. (2013). Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. Journal of Diabetes Investigation,4(1), 4–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rubler, S., Dlugash, J., Yuceoglu, Y. Z., Kumral, T., Branwood, A. W., & Grishman, A. (1972). New type of cardiomyopathy associated with diabetic glomerulosclerosis. American Journal of Cardiology,30(6), 595–602.

    Article  CAS  PubMed  Google Scholar 

  6. Kannel, W. B., & McGee, D. L. (1979). Diabetes and cardiovascular risk factors: The Framingham study. Circulation,59(1), 8–13.

    Article  CAS  PubMed  Google Scholar 

  7. Andreadou, I., Iliodromitis, E. K., Rassaf, T., Schulz, R., Papapetropoulos, A., & Ferdinandy, P. (2015). The role of gasotransmitters NO, H2S and CO in myocardial ischaemia/reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning. British Journal of Pharmacology,172(6), 1587–1606.

    Article  CAS  PubMed  Google Scholar 

  8. Lambert, J. P., Nicholson, C. K., Amin, H., Amin, S., & Calvert, J. W. (2014). Hydrogen sulfide provides cardioprotection against myocardial/ischemia reperfusion injury in the diabetic state through the activation of the RISK pathway. Med. Gas Res.,4, 20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Peake, B. F., Nicholson, C. K., Lambert, J. P., Hood, R. L., Amin, H., Amin, S., et al. (2013). Hydrogen sulfide preconditions the db/db diabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner. American Journal of Physiology-Heart and Circulatory Physiology,304(9), H1215–H1224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Guo, R., Wu, Z., Jiang, J., Liu, C., Wu, B., Li, X., et al. (2017). New mechanism of lipotoxicity in diabetic cardiomyopathy: Deficiency of Endogenous H2S Production and ER stress. Mechanisms of Ageing and Development,162, 46–52.

    Article  CAS  PubMed  Google Scholar 

  11. Zhou, X., An, G., & Lu, X. (2015). Hydrogen sulfide attenuates the development of diabetic cardiomyopathy. Clinical Science,128(5), 325–335.

    Article  CAS  PubMed  Google Scholar 

  12. Mensah, K., Mocanu, M. M., & Yellon, D. M. (2005). Failure to protect the myocardium against ischemia/reperfusion injury after chronic atorvastatin treatment is recaptured by acute atorvastatin treatment: A potential role for phosphatase and tensin homolog deleted on chromosome ten. Journal of the American College of Cardiology,45(8), 1287–1291.

    Article  CAS  PubMed  Google Scholar 

  13. Kurian, G. A., Sachu, P., & Thomas, V. (2005). Effect of aqueous extract of Desmodium Gangeticum root in the severity of isoproterenol induced Myocardial infarcted rats. Journal of Ethnopharmacology,97(3), 457–461.

    Article  PubMed  Google Scholar 

  14. Noltmann, E. A., Gubler, C. J., & Kuby, S. A. (1961). Glucose 6-phosphate dehydrogenase (Zwischenferment) I. Isolation of the crystalline enzyme from yeast. Journal of Biologiocal Chemistry,236(5), 1225–1230.

    CAS  Google Scholar 

  15. Bergmeyer, H. U., Grassl, M., & Walter, H. E. (1983). Reagents for enzymatic analysis. Methods of Enzymatic Analysis,2, 185–223.

    Google Scholar 

  16. Gostimskaya, I., & Galkin, A. (2010). Preparation of highly coupled rat heart mitochondria. Journal of Visualized Experiments,43, 2202.

    Google Scholar 

  17. Frazier, A. E., & Thorburn, D. R. (2012). Biochemical analyses of the electron transport chain complexes by spectrophotometry. Methods in Molecular Biology,837, 49–62.

    Article  CAS  PubMed  Google Scholar 

  18. Fraga, C. G., Leibovitz, B. E., & Tappel, A. L. (1988). Lipid peroxidation measured as thiobarbituric acid reactive substances in tissue slices: Characterization and comparison with homogenates and microsomes. Free Radical Biology and Medicine,4, 155–161.

    Article  CAS  PubMed  Google Scholar 

  19. Ansari, S. B., & Kurian, G. A. (2016). Hydrogen sulfide modulates sub-cellular susceptibility to oxidative stress induced by myocardial ischemic reperfusion injury. Chemico-Biological Interactions,252, 28–35.

    Article  CAS  PubMed  Google Scholar 

  20. Denton, D., Mills, K., & Kumar, S. (2008). Methods and protocols for studying cell death in Drosophila. Methods in Enzymology,446, 17–37.

    Article  CAS  PubMed  Google Scholar 

  21. Stepien, P. P., & Pieniazek, N. J. (1973). The use of the l-serine sulfhydrylase assay for the estimation of cystathionine b-synthase. Analytical Biochemistry,54, 294–299.

    Article  CAS  PubMed  Google Scholar 

  22. Lee, C. H., Hwang, J. H., Lee, Y. S., & Cho, K. S. (1995). Purification and characterization of mouse liver rhodanase. Journal of Biochemistry and Molecular Biology,28, 170–176.

    CAS  Google Scholar 

  23. Elrod, J. W., Calvert, J. W., Morrison, J., Doeller, J. E., Kraus, D. W., Tao, L., et al. (2007). Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proceedings of the National Academy of Sciences of the United States of America,104(39), 5560–15565.

    Article  Google Scholar 

  24. Karwi, Q. G., Bornbaum, J., Boengler, K., Torregrossa, R., Whiteman, M., Wood, M. E., et al. (2017). AP39, a mitochondria-targeting hydrogen sulfide (H2S) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling. British Journal of Pharmacology,174, 287–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chatzianastasiou, A., Bibli, S. I., Andreadou, I., Efentakis, P., Kaludercic, N., Wood, M. E., et al. (2016). Cardioprotection by H2S donors: nitric oxide-dependent and -independent mechanisms. Journal of Pharmacology and Experimental Therapeutics,106, 432–442.

    Google Scholar 

  26. Sivarajah, A., Collino, M., Yasin, M., Benetti, E., Gallicchio, M., Mazzon, E., et al. (2009). Anti-apoptotic and anti-inflammatory effects of hydrogen sulfide in a rat model of regional myocardial I/R. Shock,31, 267–274.

    Article  CAS  PubMed  Google Scholar 

  27. Yao, L. L., Huang, X. W., Wang, Y. G., Cao, Y. X., Zhang, C. C., & Zhu, Y. C. (2010). Hydrogen sulfide protects cardiomyocytes from hypoxia/reoxygenation-induced apoptosis by preventing GSK-3beta-dependent opening of mPTP. American Journal of Physiology-Heart and Circulatory Physiology,298, H1310–H1319.

    Article  CAS  PubMed  Google Scholar 

  28. Buchanan, J., Mazumder, P. K., Hu, P., Chakrabarti, G., Roberts, M. W., Yun, U. J., et al. (2005). Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology,146, 5341–5349.

    Article  CAS  PubMed  Google Scholar 

  29. Ouwens, D. M., Boer, C., Fodor, M., De Galan, P., Heine, R. J., Maassen, J. A., et al. (2005). Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats. Diabetologia,48, 1229–1237.

    Article  CAS  PubMed  Google Scholar 

  30. Travers, J. G., Kamal, F. A., Robbins, J., Yutzey, K. E., & Blaxall, B. C. (2016). Cardiac fibrosis: the fibroblast awakens. Circulation Research,118(6), 1021–1040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Frangogiannis, N. G. (2012). Regulation of the inflammatory response in cardiac repair. Circulation Research,110, 159–173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yang, Z., Tian, Y., Liu, Y., Hennessy, S., Kron, I. L., & French, B. A. (2013). Acute hyperglycemia abolishes ischemic preconditioning by inhibiting Akt phosphorylation: Normalizing blood glucose before ischemia restores ischemic preconditioning. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2013/329183.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Jiang, H., Xiao, J., Kang, B., Zhu, X., Xin, N., & Wang, Z. (2016). PI3K/SGK1/GSK3β signaling pathway is involved in inhibition of autophagy in neonatal rat cardiomyocytes exposed to hypoxia/reoxygenation by hydrogen sulfide. Experimental Cell Research,345(2), 134–140.

    Article  CAS  PubMed  Google Scholar 

  34. Heydrick, S. J., Jullien, D., Gautier, N., Tanti, J. F., Giorgetti, S., Van Obberghen, E., et al. (1993). Defect in skeletal muscle phosphatidylinositol-3-kinase in obese insulin-resistant mice. Journal of Clinical Investigation,91(4), 1358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Boudina, S., Sena, S., O’Neill, B. T., Tathireddy, P., Young, M. E., & Abel, E. D. (2005). Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation,112, 2686–2695.

    Article  PubMed  Google Scholar 

  36. Bugger, H., Boudina, S., Hu, X. X., Tuinei, J., Zaha, V. G., Theobald, H. A., et al. (2008). Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3. Diabetes,57, 2924–2932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Duncan, J. G., Fong, J. L., Medeiros, D. M., Finck, B. N., & Kelly, D. P. (2007). Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-alpha/PGC-1alpha gene regulatory pathway. Circulation,115, 909–917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ansari, M., Gopalakrishnan, S., & Kurian, G. A. (2019). Streptozotocin-induced type II diabetic rat administered with nonobesogenic high-fat diet is highly susceptible to myocardial ischemia–reperfusion injury: An insight into the function of mitochondria. Journal of Cellular Physiology,234(4), 4104–4114.

    Article  CAS  PubMed  Google Scholar 

  39. Tian, D., Dong, J., Jin, S., Teng, X., & Wu, Y. (2017). Endogenous hydrogen sulfide-mediated MAPK inhibition preserves endothelial function through TXNIP signaling. Free Radical Biology and Medicine,110, 291–299.

    Article  CAS  PubMed  Google Scholar 

  40. Xie, Z. Z., Liu, Y., & Bian, J. S. (2016). Hydrogen sulfide and cellular redox homeostasis. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2016/6043038.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Mahalakshmi, A., & Kurian, G. A. (2018). Evaluating the impact of diabetes and diabetic cardiomyopathy rat heart on the outcome of ischemia-reperfusion associated oxidative stress. Free Radical Biology and Medicine,118, 35–43.

    Article  CAS  PubMed  Google Scholar 

  42. Szabo, C., Ransy, C., Módis, K., Andriamihaja, M., Murghes, B., Coletta, C., et al. (2014). Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part I. Biochemical and physiological mechanisms. British Journal of Pharmacology,171, 2099–2122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fu, M., Zhang, W., Wu, L., Yang, G., Li, H., & Wang, R. (2012). Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production. Proceedings of the National Academy of Sciences United States of America,109(8), 2943–2948.

    Article  CAS  Google Scholar 

  44. Bravo, E., Palleschi, S., Aspichueta, P., Buqué, X., Rossi, B., Cano, A., et al. (2011). High fat diet-induced non alcoholic fatty liver disease in rats is associated with hyperhomocysteinemia caused by down regulation of the transsulphuration pathway. Lipids in Health and Disease,10(1), 60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors sincerely thank the Department of Science and Technology (DST/INSPIRE Fellowship/2013/326). The authors also place on record their thanks to Kausthubh R. for his editing of this manuscript.

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  1. Vascular Biology Lab (ASK 1, 117), School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, India

    Mahalakshmi Ansari & Gino A. Kurian

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  1. Mahalakshmi Ansari
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  2. Gino A. Kurian
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Contributions

Dr. Gino A Kurian has contributed to the design and implementation of the research, the interpretation of the results, and writing of the manuscript. Ms. Mahalakshmi has processed the experimental data, performed analysis, drafted the manuscript, designed figures and tables, and compiled the literature sources.

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Correspondence to Gino A. Kurian.

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Ansari, M., Kurian, G.A. Mechanism of Hydrogen Sulfide Preconditioning-Associated Protection Against Ischemia–Reperfusion Injury Differs in Diabetic Heart That Develops Myopathy. Cardiovasc Toxicol 20, 155–167 (2020). https://doi.org/10.1007/s12012-019-09542-9

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