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 (T2DN(mtWistar) and T2DN(mtFHH), respectively).
Methods: Myocardial infarct size was measured in Wistar, T2DN(mtWistar), and T2DN(mtFHH) 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 T2DN(mtWistar) 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 T2DN(mtFHH) rats (60 ± 2%, n = 8). N-acetylcysteine applied during isoflurane treatment restored APC in T2DN(mtFHH) (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 T2DN(mtWistar) but not in T2DN(mtFHH) cardiomyocytes. Isoflurane increased flavoprotein and 5-(and-6)-chloromethyl-2',7'-dichlorofluorescein fluorescence intensity in all rat strains, with the greatest effect in T2DN(mtFHH) 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.