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
Endothelium-Dependent Relaxing Factors
Male
Mitogen-Activated Protein Kinase 1
0301 basic medicine
Nitrates
Endothelins
Blotting, Western
NF-kappa B
Blood Pressure
Enzyme-Linked Immunosorbent Assay
Muscle, Smooth, Vascular
Mesenteric Arteries
3. Good health
03 medical and health sciences
Diabetes Mellitus, Type 2
Eicosapentaenoic Acid
Isometric Contraction
Chronic Disease
Animals
Endothelium, Vascular
Blood Chemical Analysis
Diabetic Angiopathies
Nitrites
DOI:
10.1124/jpet.108.148718
Publication Date:
2009-01-23T02:12:21Z
AUTHORS (5)
ABSTRACT
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.
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