Chronic Co-Administration of Sepiapterin and L-Citrulline Ameliorates Diabetic Cardiomyopathy and Myocardial Ischemia/Reperfusion Injury in Obese Type 2 Diabetic Mice
| Autor: | Juan Fang, David X. Zhang, Judy R. Kersten, Zeljko J. Bosnjak, Zhi-Dong Ge, Thorsten M. Leucker, Mark Paterson, David C. Warltier, Shelley L. Baumgardt |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Time Factors Diabetic Cardiomyopathies Myocardial Infarction Mice Obese 030204 cardiovascular system & hematology Ventricular Function Left chemistry.chemical_compound 0302 clinical medicine Diabetic cardiomyopathy Phosphorylation Cells Cultured Ejection fraction biology Age Factors Tetrahydrobiopterin Coronary Vessels Nitric oxide synthase Vasodilation Drug Therapy Combination Cardiology and Cardiovascular Medicine medicine.drug medicine.medical_specialty Sepiapterin Cardiotonic Agents Nitric Oxide Synthase Type III Ischemia Biopterin Myocardial Reperfusion Injury Nitric Oxide Drug Administration Schedule Article 03 medical and health sciences Internal medicine Coronary Circulation medicine Animals Obesity business.industry Myocardium Endothelial Cells Isolated Heart Preparation medicine.disease Pterins Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology chemistry Diabetes Mellitus Type 2 biology.protein Citrulline Protein Multimerization business Reperfusion injury |
| Zdroj: | Circulation. Heart failure. 9(1) |
| ISSN: | 1941-3297 |
| Popis: | 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 ±d P /d t 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. |
| Databáze: | OpenAIRE |
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