Inhibition of nitric oxide synthase uncoupling by sepiapterin improves left ventricular function in streptozotocin-induced diabetic mice

Clin Exp Pharmacol Physiol. 2011 Aug;38(8):485-93. doi: 10.1111/j.1440-1681.2011.05535.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopterin / analogs & derivatives
  • Biopterin / analysis
  • Biopterin / physiology
  • Cardiotonic Agents / pharmacology
  • Cardiotonic Agents / therapeutic use
  • Coenzymes / pharmacology
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetic Cardiomyopathies / chemically induced
  • Diabetic Cardiomyopathies / drug therapy*
  • Diabetic Cardiomyopathies / physiopathology
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Lipid Peroxidation / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / analysis
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / physiology*
  • Pterins / pharmacology*
  • Pterins / therapeutic use
  • Tyrosine / analogs & derivatives
  • Tyrosine / analysis
  • Ventricular Dysfunction, Left / drug therapy*
  • Ventricular Dysfunction, Left / enzymology
  • Ventricular Function, Left / drug effects*
  • Ventricular Function, Left / physiology

Substances

  • Cardiotonic Agents
  • Coenzymes
  • Enzyme Inhibitors
  • Pterins
  • Biopterin
  • Nitric Oxide
  • 3-nitrotyrosine
  • Tyrosine
  • 7,8-dihydrobiopterin
  • sepiapterin
  • Nitric Oxide Synthase
  • sapropterin