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.

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.

• Authors: Shelley L Baumgardt, Mark Paterson, Thorsten M Leucker, Juan Fang, David X Zhang, Zeljko J Bosnjak, David C Warltier, Judy R Kersten, Zhi-Dong Ge
• Journal: Circulation. Heart failure (Circ Heart Fail) Vol. 9 Issue 1 Pg. e002424 (Jan 2016) ISSN: 1941-3297 [Electronic] United States
• PMID: 26763290 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 American Heart Association, Inc.

Chemical References

• Cardiotonic Agents
• Pterins
• Biopterin
• Citrulline
• Nitric Oxide
• sepiapterin
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• sapropterin

Topics

• Age Factors
• Animals
• Biopterin (analogs & derivatives, metabolism)
• Cardiotonic Agents (administration & dosage)
• Cells, Cultured
• Citrulline (administration & dosage)
• Coronary Circulation (drug effects)
• Coronary Vessels (drug effects, metabolism, physiopathology)
• Diabetes Mellitus, Type 2 (complications, drug therapy, metabolism)
• Diabetic Cardiomyopathies (etiology, metabolism, pathology, physiopathology, prevention & control)
• Disease Models, Animal
• Drug Administration Schedule
• Drug Therapy, Combination
• Endothelial Cells (drug effects, metabolism)
• Isolated Heart Preparation
• Mice, Inbred C57BL
• Mice, Obese
• Myocardial Infarction (etiology, metabolism, pathology, physiopathology, prevention & control)
• Myocardial Reperfusion Injury (etiology, metabolism, pathology, physiopathology, prevention & control)
• Myocardium (metabolism, pathology)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Obesity (complications)
• Phosphorylation
• Protein Multimerization
• Pterins (administration & dosage)
• Time Factors
• Vasodilation (drug effects)
• Ventricular Function, Left (drug effects)