Reversal of inducible nitric oxide synthase uncoupling unmasks tolerance to ischemia/reperfusion injury in the diabetic rat heart.

Abstract

The diabetic heart is known to be susceptible to ischemia/reperfusion (I/R) injury by increased oxidative stress. Although oxidative stress upregulates inducible nitric oxide (iNOS), the role of iNOS in I/R injury in the diabetic heart has been poorly understood. Because iNOS-derived nitric oxide (NO) plays a crucial role in cardioprotection against I/R injury, we hypothesized that inhibition of iNOS uncoupling would restore tolerance to I/R injury in the diabetic heart. The present study demonstrated that iNOS-derived superoxide generation was reduced, and that the NO bioavailability was increased, by treatment with the NOS-cofactor, tetrahydrobiopterin (BH4), before I/R in the hearts isolated from diabetic rats. This was associated with a reduction of infarct size and improvement of left ventricular (LV) function after I/R. The cardioprotective effect of BH4 was abrogated by treatment with a thiol reducing agent dithiothreitol (DTT), but not a NO-sensitive guanylyl cyclase inhibitor ODQ, suggesting that iNOS-derived NO-mediated cardioprotection occurs through protein S-nitrosylation but not cGMP-dependent signaling in the diabetic heart. Indeed, protein S-nitrosylation was increased by treatment with BH4 in the diabetic heart and was inhibited by DTT. These results suggest that the inhibition of iNOS uncoupling unmasks tolerance to I/R injury through enhanced protein S-nitrosylation in the diabetic rat heart.

• Authors: Toru Okazaki, Hajime Otani, Takayuki Shimazu, Kei Yoshioka, Masanori Fujita, Tayo Katano, Seiji Ito, Toshiji Iwasaka
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 50 Issue 3 Pg. 534-44 (Mar 2011) ISSN: 1095-8584 [Electronic] England
• PMID: 21182845 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ltd. All rights reserved.

Chemical References

• 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
• Imines
• N-((3-(aminomethyl)phenyl)methyl)ethanimidamide
• Oxadiazoles
• Quinoxalines
• Superoxides
• Biopterin
• Nitric Oxide
• 3-nitrotyrosine
• Tyrosine
• Tiopronin
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• sapropterin
• Cyclic GMP
• Dithiothreitol

Topics

• Animals
• Biopterin (analogs & derivatives, metabolism, pharmacology)
• Cyclic GMP (metabolism)
• Diabetes Complications (enzymology, metabolism, pathology)
• Diabetes Mellitus, Experimental (enzymology, metabolism, pathology)
• Dithiothreitol (pharmacology)
• Imines (pharmacology)
• Male
• Myocardial Reperfusion Injury (enzymology, metabolism, pathology)
• Nitric Oxide (metabolism, pharmacology)
• Nitric Oxide Synthase Type II (biosynthesis, genetics, metabolism)
• Oxadiazoles (pharmacology)
• Oxidative Stress (drug effects)
• Quinoxalines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Superoxides (metabolism)
• Tiopronin (pharmacology)
• Tyrosine (analogs & derivatives, metabolism)
• Up-Regulation
• Ventricular Function, Left (drug effects)