Newly Published
Perioperative Medicine  |   October 2017
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
Author Notes
  • From 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.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Z.-D.G. and Y.L. contributed equally to this work.
    Z.-D.G. and Y.L. contributed equally to this work.×
  • Submitted for publication March 3, 2017. Accepted for publication September 14, 2017.
    Submitted for publication March 3, 2017. Accepted for publication September 14, 2017.×
  • Acknowledgments: We thank John A. Auchampach, Ph.D., and Tina C. Wan, Ph.D. (both from Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin), for their VisualSonics echocardiography; Garrett J. Gross, Ph.D. (Department of Pharmacology and Toxicology, Medical College of Wisconsin), for his powerlab data acquisition system; Mark Paterson, B.S. (Department of Physiology, Medical College of Wisconsin); and David Schwabe, B.S., and John Tessmer, B.S. (both from Department of Anesthesiology, Medical College of Wisconsin), for their excellent technical assistance.
    Acknowledgments: We thank John A. Auchampach, Ph.D., and Tina C. Wan, Ph.D. (both from Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin), for their VisualSonics echocardiography; Garrett J. Gross, Ph.D. (Department of Pharmacology and Toxicology, Medical College of Wisconsin), for his powerlab data acquisition system; Mark Paterson, B.S. (Department of Physiology, Medical College of Wisconsin); and David Schwabe, B.S., and John Tessmer, B.S. (both from Department of Anesthesiology, Medical College of Wisconsin), for their excellent technical assistance.×
  • Research Support: This work was supported, in part, by National Institutes of Health grant Nos. P01GM 066730 (to Drs. Liang and Bosnjak) and HL 063705 (to Dr. Kersten) from the U.S. Public Health Services, Bethesda, Maryland.
    Research Support: This work was supported, in part, by National Institutes of Health grant Nos. P01GM 066730 (to Drs. Liang and Bosnjak) and HL 063705 (to Dr. Kersten) from the U.S. Public Health Services, Bethesda, Maryland.×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Ge: Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, Wisconsin 53226. Wilson.ge99@gmail.com. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Cardiovascular Anesthesia / Endocrine and Metabolic Systems / Pharmacology
Perioperative Medicine   |   October 2017
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
Anesthesiology Newly Published on October 19, 2017. doi:10.1097/ALN.0000000000001926
Anesthesiology Newly Published on October 19, 2017. doi:10.1097/ALN.0000000000001926
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 II 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 II diabetic db/db mice is associated with aberrant regulation of microRNA-21, endothelial nitric-oxide synthase, and mitochondrial respiratory complex I.