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.
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)-kappaB 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-kappaB activation, and reducing COX-2 expression.
Matsumoto
Takayuki
T
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
Nakayama
Naoaki
N
Ishida
Keiko
K
Kobayashi
Tsuneo
T
Kamata
Katsuo
K
D000818:Animals; D001774:Blood Chemical Analysis; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002908:Chronic Disease; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000503:physiopathology / Q000517:prevention & control; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D016232:Endothelins / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010766:Phosphorylation; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF
D016232:Endothelins; D045462:Endothelium-Dependent Relaxing Factors; D016328:NF-kappa B; D009566:Nitrates; D009573:Nitrites; D011453:Prostaglandins; D015118:Eicosapentaenoic Acid; D019950:Mitogen-Activated Protein Kinase 1