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Anesthesiology:
doi: 10.1097/ALN.0000000000000107
Perioperative Medicine: Basic Science

Cardioprotection during Diabetes: The Role of Mitochondrial DNA

Muravyeva, Maria M.D., Ph.D.; Baotic, Ines M.D.; Bienengraeber, Martin Ph.D.; Lazar, Jozef Ph.D.; Bosnjak, Zeljko J. Ph.D.; Sedlic, Filip M.D., Ph.D.; Warltier, David C. M.D., Ph.D.; Kersten, Judy R. M.D.

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Abstract

Background: Diabetes alters mitochondrial bioenergetics and consequently disrupts cardioprotective signaling. The authors investigated whether mitochondrial DNA (mtDNA) modulates anesthetic preconditioning (APC) and cardiac susceptibility to ischemia–reperfusion injury by using two strains of rats, both sharing nuclear genome of type 2 diabetes mellitus (T2DN) rats and having distinct mitochondrial genomes of Wistar and fawn-hooded hypertensive (FHH) rat strains (T2DNmtWistar and T2DNmtFHH, respectively).
Methods: Myocardial infarct size was measured in Wistar, T2DNmtWistar, and T2DNmtFHH rats with or without APC (1.4% isoflurane) in the presence or absence of antioxidant N-acetylcysteine. Flavoprotein fluorescence intensity, a marker of mitochondrial redox state, 5-(and-6)-chloromethyl-2’,7’-dichlorofluorescein fluorescence intensity, a marker of reactive oxygen species generation, and mitochondrial permeability transition pore opening were assessed in isolated rat ventricular cardiomyocytes with or without isoflurane (0.5 mmol/l).
Results: Myocardial infarct size was decreased by APC in Wistar and T2DNmtWistar rats (to 42 ± 6%, n = 8; and 44 ± 7%, n = 8; of risk area, respectively) compared with their respective controls (60 ± 3%, n = 6; and 59 ± 9%, n = 7), but not in T2DNmtFHH rats (60 ± 2%, n = 8). N-acetylcysteine applied during isoflurane treatment restored APC in T2DNmtFHH (39 ± 6%, n = 7; and 38 ± 5%, n = 7; 150 and 75 mg/kg N-acetylcysteine, respectively), but abolished protection in control rats (54 ± 8%, n = 6). Similar to the data on infarct size, APC delayed mitochondrial permeability transition pore opening in T2DNmtWistar but not in T2DNmtFHH cardiomyocytes. Isoflurane increased flavoprotein and 5-(and-6)-chloromethyl-2’,7’-dichlorofluorescein fluorescence intensity in all rat strains, with the greatest effect in T2DNmtFHH cardiomyocytes.
Conclusion: Differences in the mitochondrial genome modulate isoflurane-induced generation of reactive oxygen species which translates into differential susceptibility to APC and ischemia–reperfusion injury in diabetic rats.

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