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Chronic Co-Administration of Sepiapterin and L-Citrulline Ameliorates Diabetic Cardiomyopathy and Myocardial Ischemia/Reperfusion Injury in Obese Type 2 Diabetic Mice. Circ Heart Fail 2016 Jan;9(1):e002424

Date

01/15/2016

Pubmed ID

26763290

Pubmed Central ID

PMC4714787

DOI

10.1161/CIRCHEARTFAILURE.115.002424

Scopus ID

2-s2.0-84955258675   26 Citations

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.

Author List

Baumgardt SL, Paterson M, Leucker TM, Fang J, Zhang DX, Bosnjak ZJ, Warltier DC, Kersten JR, Ge ZD

Authors

Zeljko J. Bosnjak PhD Professor in the Medicine department at Medical College of Wisconsin
David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Age Factors
Animals
Biopterin
Cardiotonic Agents
Cells, Cultured
Citrulline
Coronary Circulation
Coronary Vessels
Diabetes Mellitus, Type 2
Diabetic Cardiomyopathies
Disease Models, Animal
Drug Administration Schedule
Drug Therapy, Combination
Endothelial Cells
Isolated Heart Preparation
Mice, Inbred C57BL
Mice, Obese
Myocardial Infarction
Myocardial Reperfusion Injury
Myocardium
Nitric Oxide
Nitric Oxide Synthase Type III
Obesity
Phosphorylation
Protein Multimerization
Pterins
Time Factors
Vasodilation
Ventricular Function, Left
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