Related Experiment Videos
Failure of Isoflurane Cardiac Preconditioning in Obese Type 2 Diabetic Mice Involves Aberrant Regulation of
Zhi-Dong Ge1, Yingchuan Li, Shigang Qiao
1From the Departments of Anesthesiology (Z.-D.G., S.Q., X.B., D.C.W., J.R.K., Z.J.B.) and Physiology (Y.L., Z.J.B., M.L.), Medical College of Wisconsin, Milwaukee, Wisconsin. Current affiliation: Department of Ophthalmology, Stanford University School of Medicine, Stanford, California (Z.-D.G.).
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.
Insights
Diabetes impairs the cardioprotective effects of isoflurane anesthesia. This study found that in type 2 diabetic mice, isoflurane failed to protect the heart due to disrupted microRNA-21 and mitochondrial function.
Area of Science:
- Anesthesiology
- Cardiovascular Biology
- Metabolic Diseases
Background:
- Diabetes mellitus significantly impairs the cardioprotective mechanisms of volatile anesthetics.
- The precise molecular pathways underlying this impairment remain incompletely understood.
- Investigating the role of specific molecular targets is crucial for understanding anesthetic responses in diabetic patients.
Purpose of the Study:
- To investigate the regulatory impact of isoflurane on microRNA-21 (miR-21), endothelial nitric-oxide synthase (eNOS), and mitochondrial respiratory complex I.
- To elucidate the mechanisms by which type 2 diabetes mellitus affects the cardioprotective properties of isoflurane.
Main Methods:
- Myocardial ischemia/reperfusion injury was induced in type 2 diabetic (db/db) and control (C57BL/6) mice.
- Isoflurane was administered prior to ischemia, with and without preconditioning.
- Cardiac miR-21 levels, eNOS dimer/monomer ratios, and mitochondrial nicotinamide adenine dinucleotide (NAD+) fluorescence were quantified.
Main Results:
- Isoflurane preconditioning improved cardiac function and reduced injury in control mice but not in diabetic mice.
- In control mice, isoflurane increased miR-21, eNOS dimerization, and decreased mitochondrial NAD+.
- These effects were absent in diabetic mice, and miR-21 knockout abolished the benefits of isoflurane.
Conclusions:
- The failure of isoflurane-mediated cardiac preconditioning in type 2 diabetic mice is linked to dysregulated miR-21, eNOS, and mitochondrial complex I.
- Aberrant molecular signaling pathways in diabetes interfere with the protective effects of isoflurane.
- Targeting these pathways may restore anesthetic cardioprotection in diabetic patients.