title: Chronic Co-Administration of Sepiapterin and L-Citrulline Ameliorates Diabetic Cardiomyopathy and Myocardial Ischemia/Reperfusion Injury in Obese Type 2 Diabetic Mice.
abstract: BACKGROUND
  Diabetic heart disease is associated with tetrahydrobiopterin oxidation and high arginase activity, leading to endothelial nitric oxide synthase dysfunction. Sepiapterin (SEP) is a tetrahydrobiopterin precursor, and L-citrulline (L-Cit) is converted to endothelial nitric oxide synthase substrate, L-arginine. Whether SEP and L-Cit are effective at reducing diabetic heart disease is not known. The present study examined the effects of SEP and L-Cit on diabetic cardiomyopathy and ischemia/reperfusion injury in obese type 2 diabetic mice.
  
  
  RESULTS
  Db/db and C57BLKS/J mice at 6 to 8 weeks of age received vehicle, SEP, or L-Cit orally alone or in combination for 8 weeks. Cardiac function was evaluated with echocardiography. Db/db mice displayed hyperglycemia, obesity, and normal blood pressure and cardiac function compared with C57BLKS/J mice at 6 to 8 weeks of age. After vehicle treatment for 8 weeks, db/db mice had reduced ejection fraction, mitral E/A ratio, endothelium-dependent relaxation of coronary arteries, tetrahydrobiopterin concentrations, ratio of endothelial nitric oxide synthase dimers/monomers, and nitric oxide levels compared with vehicle-treated C57BLKS/J mice. These detrimental effects of diabetes mellitus were abrogated by co-administration of SEP and L-Cit. Myocardial infarct size was increased, and coronary flow rate and ± dP/dt were decreased during reperfusion in vehicle-treated db/db mice subjected to ischemia/reperfusion injury compared with control mice. Co-administration of SEP and L-Cit decreased infarct size and improved coronary flow rate and cardiac function in both C57BLKS/J and db/db mice.
  
  
  CONCLUSIONS
  Co-administration of SEP and L-Cit limits diabetic cardiomyopathy and ischemia/reperfusion injury in db/db mice through a tetrahydrobiopterin/endothelial nitric oxide synthase/nitric oxide pathway.
authors.affiliation: From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.).
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Baumgardt
authors.affiliation: From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.).
authors.forename: Mark
authors.initials: M
authors.lastname: Paterson
authors.affiliation: From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.).
authors.forename: Thorsten M
authors.initials: TM
authors.lastname: Leucker
authors.affiliation: From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.).
authors.forename: Juan
authors.initials: J
authors.lastname: Fang
authors.affiliation: From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.).
authors.forename: David X
authors.initials: DX
authors.lastname: Zhang
authors.affiliation: From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.).
authors.forename: Zeljko J
authors.initials: ZJ
authors.lastname: Bosnjak
authors.affiliation: From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.).
authors.forename: David C
authors.initials: DC
authors.lastname: Warltier
authors.affiliation: From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.).
authors.forename: Judy R
authors.initials: JR
authors.lastname: Kersten
authors.affiliation: From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.). Wilson.ge99@gmail.com.
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Ge
mesh_terms: D000367:Age Factors; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D002478:Cells, Cultured; D002956:Citrulline / Q000008:administration & dosage*; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D000067268:Isolated Heart Preparation; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000150:complications*; D010766:Phosphorylation; D055503:Protein Multimerization; D011622:Pterins / Q000008:administration & dosage*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D011622:Pterins; D001708:Biopterins; D002956:Citrulline; D009569:Nitric Oxide; C016727:sepiapterin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C003402:sapropterin
keywords: diabetic cardiomyopathy; ischemia reperfusion injury; nitric oxide synthase; tetrahydrobiopterin; type 2 diabetes mellitus