Failure of Isoflurane Cardiac Preconditioning in Obese Type 2 Diabetic Mice Involves Aberrant Regulation of MicroRNA-21, Endothelial Nitric-oxide Synthase, and Mitochondrial Complex i

Abstract

Background: Diabetes impairs the cardioprotective effect of volatile anesthetics, yet the mechanisms are still murky. We examined the regulatory effect of isoflurane on microRNA-21, endothelial nitric-oxide synthase, and mitochondrial respiratory complex I in type 2 diabetic mice. Methods: Myocardial ischemia/reperfusion injury was produced in obese type 2 diabetic (db/db) and C57BL/6 control mice ex vivo in the presence or absence of isoflurane administered before ischemia. Cardiac microRNA-21 was quantified by real-time quantitative reverse transcriptional-polymerase chain reaction. The dimers and monomers of endothelial nitric-oxide synthase were measured by Western blot analysis. Mitochondrial nicotinamide adenine dinucleotide fluorescence was determined in Langendorff-perfused hearts. Results: Body weight and fasting blood glucose were greater in db/db than C57BL/6 mice. Isoflurane decreased left ventricular end-diastolic pressure from 35 ± 8 mmHg in control to 23 ± 9 mmHg (P = 0.019, n = 8 mice/group, mean ± SD) and elevated ±dP/dt 2 h after post-ischemic reperfusion in C57BL/6 mice. These beneficial effects of isoflurane were lost in db/db mice. Isoflurane elevated microRNA-21 and the ratio of endothelial nitric-oxide synthase dimers/monomers and decreased mitochondrial nicotinamide adenine dinucleotide levels 5 min after ischemia in C57BL/6 but not db/db mice. MicroRNA-21 knockout blocked these favorable effects of isoflurane, whereas endothelial nitric-oxide synthase knockout had no effect on the expression of microRNA-21 but blocked the inhibitory effect of isoflurane preconditioning on nicotinamide adenine dinucleotide. Conclusions: Failure of isoflurane cardiac preconditioning in obese type 2 diabetic db/db mice is associated with aberrant regulation of microRNA-21, endothelial nitric-oxide synthase, and mitochondrial respiratory complex I.