Mitochondrial dysfunction plays a key role in the abrogation of cardioprotection by sodium hydrosulfide post-conditioning in diabetic cardiomyopathy rat heart
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Our previous study demonstrated that hydrogen sulfide post-conditioning (HPOC) renders cardioprotection against ischemia-reperfusion (I/R) injury in normal rat by preserving mitochondria. But its efficacy in ameliorating I/R in the diabetic heart with (DCM) or without cardiomyopathy (DM) is unclear and is the focus of the present study. Normal (N), diabetes mellitus (streptozotocin, 35 mg/kg; normal diet), and DCM (streptozotocin, 35 mg/kg; high-fat diet) rats were subjected to I/R (30 min global ischemia followed by 60 min reperfusion) in presence and absence of HPOC using ex vivo Langendorff perfusion system. At the end of heart perfusion, subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) fractions from the tissue were isolated and measured for the ATP production, electron transport chain (ETC) enzyme activity, and membrane potential. The prominent I/R-associated injury in DCM rat was not subsequently attenuated by HPOC protocol unlike in the normal or diabetic rat heart (latter rat heart showed moderate protection) (HPOC recovery on infarct size: N 75% vs. DM 63% vs. DCM 48%). The baseline ATP content and subsequent ATP-producing capacity in DCM rat heart were low as compared with those in normal or DM rat heart, especially in SSM. HPOC protocol reversed the I/R-induced low mitochondrial ATP content and low ATP-producing capacity (both in non-energized and energized with glutamate/malate) significantly in normal and DM hearts, but not in DCM heart. Moreover in DCM, decreased activity of mitochondrial electron chain enzymes (complexes I, II, III, and IV) in SSM (26%, 88%, 57%, and 17%) and IFM (76%, 89%, 60%, and 13%) from sham control was maintained even after the conditioning of heart with hydrogen sulfide donor. Results altogether suggest that significantly higher levels of perturbing mitochondria in DCM rat heart underline the deteriorated cardiac recovery by HPOC.
KeywordsDiabetes mellitus Diabetic cardiomyopathy Ischemia-reperfusion injury Subsarcolemmal mitochondria Interfibrillar mitochondria
The authors sincerely thank the Department of Science and Technology for providing INSPIRE fellowship (DST/INSPIRE Fellowship/2013/326).
Dr. Gino A Kurian has designed the work and helped in data interpretation and writing the manuscript. Ms. Mahalakshmi A has executed the experiments, analyzed the data, interpreted the results, wrote the manuscript, and compiled the literature sources.
Compliance with ethical standards
All procedures for the handling of the animals during the investigations were reviewed and approved by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA Approval No. 300/SASTRA/IAEC/RPP), India.
Conflict of interest
The authors declare that they have no conflicts of interest.
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