title: 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.affiliation: Second Department of Internal Medicine, Kansai Medical University, Moriguchi City, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Okazaki
authors.forename: Hajime
authors.initials: H
authors.lastname: Otani
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shimazu
authors.forename: Kei
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujita
authors.forename: Tayo
authors.initials: T
authors.lastname: Katano
authors.forename: Seiji
authors.initials: S
authors.lastname: Ito
authors.forename: Toshiji
authors.initials: T
authors.lastname: Iwasaka
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D048909:Diabetes Complications / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004229:Dithiothreitol / Q000494:pharmacology; D007097:Imines / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D008625:Tiopronin / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D007097:Imines; C496401:N-((3-(aminomethyl)phenyl)methyl)ethanimidamide; D010069:Oxadiazoles; D011810:Quinoxalines; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D008625:Tiopronin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C003402:sapropterin; D006152:Cyclic GMP; D004229:Dithiothreitol