title: Inhibition of nitric oxide synthase uncoupling by sepiapterin improves left ventricular function in streptozotocin-induced diabetic mice.
abstract: 1. Uncoupling of nitric oxide synthase (NOS) has been implicated in the pathogenesis of left ventricular (LV) dysfunction in diabetes mellitus. In the present study, we investigated the role of NOS uncoupling in oxidative/nitrosative stress and LV dysfunction in the diabetic mouse heart. 2. Diabetes was induced in wild-type (WT), endothelial (e) NOS knockout (eNOS(-/-)), inducible (i) NOS knockout (iNOS(-/-)) and neuronal (n) NOS knockout (nNOS(-/-)) mice by streptozotocin (STZ) treatment. 3. In the diabetic heart, iNOS, but not eNOS or nNOS, expression was increased. Levels of malondialdehyde (MDA), 4-hydroxy-noneal (HNE) and nitrotyrosine (NT), as markers of oxidative/nitrosative stress, were increased in the diabetic mouse heart, but the increase in oxidative/nitrosative stress was significantly repressed in the iNOS(-/-) diabetic mouse heart. Levels of nitrite and nitrate (NO(x)), as an index of nitric oxide, bioavailability were significantly decreased in the iNOS(-/-) diabetic mouse heart. 4. Oral administration of sepiapterin (10 mg/kg per day), a precursor of tetrahydrobiopterin (BH(4)), significantly increased BH(4) and the BH(4)/BH(2) ratio in diabetic mouse heart. Similarly, sepiapterin inhibited the formation of HNE, MDA and NT in diabetic hearts from all three genotypes, but the increase in NO(x) following sepiapterin treatment was significantly attenuated in the iNOS(-/-) diabetic mouse heart. Percentage fractional shortening (FS), evaluated by echocardiography, decreased significantly in all genotypes of diabetic mice. Sepiapterin significantly increased percentage FS in diabetic mice, except in iNOS(-/-) mice. 5. These results suggest that sepiapterin inhibits uncoupling of NOS and improves LV function presumably by increasing iNOS-derived nitric oxide in the diabetic heart.
authors.affiliation: Second Department of Internal Medicine, Kansai Medical University, Moriguchi, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Jo
authors.forename: Hajime
authors.initials: H
authors.lastname: Otani
authors.forename: Fusakazu
authors.initials: F
authors.lastname: Jo
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shimazu
authors.forename: Toru
authors.initials: T
authors.lastname: Okazaki
authors.forename: Kei
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujita
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kosaki
authors.forename: Toshiji
authors.initials: T
authors.lastname: Iwasaka
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000032:analysis / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D003067:Coenzymes / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology; D058065:Diabetic Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D011622:Pterins / Q000494:pharmacology* / Q000627:therapeutic use; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000201:enzymology; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D003067:Coenzymes; D004791:Enzyme Inhibitors; D011622:Pterins; D001708:Biopterins; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; C017226:7,8-dihydrobiopterin; C016727:sepiapterin; D019001:Nitric Oxide Synthase; C003402:sapropterin