Shelley L Baumgardt1, Mark Paterson1, Thorsten M Leucker1, Juan Fang1, David X Zhang1, Zeljko J Bosnjak1, David C Warltier1, Judy R Kersten1, Zhi-Dong Ge2. 1. 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.). 2. 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.
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. METHODS AND 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.
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 diabeticmice. METHODS AND 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/dbmice 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/dbmice 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/dbmice subjected to ischemia/reperfusion injury compared with control mice. Co-administration of SEP and L-Citdecreased infarct size and improved coronary flow rate and cardiac function in both C57BLKS/J and db/dbmice. CONCLUSIONS: Co-administration of SEP and L-Cit limits diabetic cardiomyopathy and ischemia/reperfusion injury in db/dbmice through a tetrahydrobiopterin/endothelial nitric oxide synthase/nitric oxide pathway.
Authors: Jennifer K Bendall; Nicholas J Alp; Nicholas Warrick; Shijie Cai; David Adlam; Kirk Rockett; Mitsuhiro Yokoyama; Seinosuke Kawashima; Keith M Channon Journal: Circ Res Date: 2005-09-22 Impact factor: 17.367
Authors: Yanan Liu; Shelley L Baumgardt; Juan Fang; Yang Shi; Shigang Qiao; Zeljko J Bosnjak; Jeannette Vásquez-Vivar; Zhengyuan Xia; David C Warltier; Judy R Kersten; Zhi-Dong Ge Journal: Sci Rep Date: 2017-06-08 Impact factor: 4.379
Authors: Hsiang-En Wu; Shelley L Baumgardt; Juan Fang; Mark Paterson; Yanan Liu; Jianhai Du; Yang Shi; Shigang Qiao; Zeljko J Bosnjak; David C Warltier; Judy R Kersten; Zhi-Dong Ge Journal: Sci Rep Date: 2016-06-13 Impact factor: 4.379