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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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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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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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