Eicosapentaenoic Acid Improves Imbalance between Vasodilator and Vasoconstrictor Actions of Endothelium-Derived Factors in Mesenteric Arteries from Rats at Chronic Stage of Type 2 Diabetes

• Published in: The Journal of pharmacology and experimental therapeutics 2009-04, Vol.329 (1), p.324-334
• Main Authors: Matsumoto, Takayuki, Nakayama, Naoaki, Ishida, Keiko, Kobayashi, Tsuneo, Kamata, Katsuo
• Format: Article
• Language: English
• Subjects: Animals; Blood Chemical Analysis; Blood Pressure - drug effects; Blotting, Western; Chronic Disease; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Diabetic Angiopathies - physiopathology; Diabetic Angiopathies - prevention & control; Eicosapentaenoic Acid - pharmacology; Endothelins - metabolism; Endothelins - physiology; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Endothelium-Dependent Relaxing Factors - metabolism; Endothelium-Dependent Relaxing Factors - physiology; Enzyme-Linked Immunosorbent Assay; Isometric Contraction - drug effects; Male; Mesenteric Arteries - drug effects; Mesenteric Arteries - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Muscle, Smooth, Vascular - drug effects; NF-kappa B - metabolism; Nitrates - metabolism; Nitrites - metabolism; Phosphorylation; Prostaglandins - metabolism; Rats; Rats, Inbred OLETF
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.108.148718

Accumulating evidence demonstrates that dietary intake of n -3 polyunsaturated fatty acids (PUFAs) is associated with a reduced incidence of several cardiovascular diseases that involve endothelial dysfunction. However, the molecular mechanism remains unclear. We previously reported that mesenteric arteries from type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats exhibit endothelial dysfunction, leading to an imbalance between endothelium-derived vasodilators [namely, nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)] and vasoconstrictors [endothelium-derived contracting factors (EDCFs)] [namely cyclooxygenase (COX)-derived prostanoids] ( Am J Physiol Heart Circ Physiol 293:H1480–H1490, 2007). We hypothesized that treating OLETF rats with eicosapentaenoic acid (EPA), a major n -3 PUFA, may improve endothelial dysfunction by correcting this imbalance. In OLETF rats [compared with age-matched control Long-Evans Tokushima Otsuka (LETO) rats]: 1) acetylcholine (ACh)-induced (endothelium-dependent) relaxation was impaired, 2) NO- and EDHF-mediated relaxations and nitrite production were reduced, and 3) ACh-induced EDCF-mediated contraction, production of prostanoids, and the protein expressions of COX-1 and COX-2 were all increased. When OLETF rats received chronic EPA treatment long-term (300 mg/kg/day p.o. for 4 weeks), their isolated mesenteric arteries exhibited: 1) improvements in ACh-induced NO- and EDHF-mediated relaxations and COX-mediated contraction, 2) reduced EDCF- and arachidonic acid-induced contractions, 3) normalized NO metabolism, 4) suppressed production of prostanoids, 5) reduced COX-2 expression, and 6) reduced phosphoextracellular signal-regulated kinase (ERK) expression. Moreover, EPA treatment reduced both ERK2 and nuclear factor (NF)-κB activities in isolated OLETF aortas. We propose that EPA ameliorates endothelial dysfunction in OLETF rats by correcting the imbalance between endothelium-derived factors, at least partly, by inhibiting ERK, decreasing NF-κB activation, and reducing COX-2 expression.