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

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)-B 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-B activation, and reducing COX-2 expression.Vascular tone is tightly regulated by endothelium-derived factors. These include relaxing factors (EDRFs) such as nitric oxide (NO), hyperpolarizing factors (EDHFs), and contracting factors (EDCFs) (Pieper, 1998;Busse et al., 2002;Félétou and Vanhoutte, 2004;Cohen, 2005;Vanhoutte et al., 2005).

The differential effects of EPA and DHA on cardiovascular risk factors

“…Both EPA and DHA increased 3-series prostacyclin production by endothelial cells to the same extent without affecting 2-series prostacyclin levels, suggesting a retroconversion from DHA to EPA (124) . In addition, EPA was shown to increase acetylcholine-induced endothelium-dependent hyperpolarising factor-mediated vasodilation in diabetic rats (125) . Endothelium-independent vasodilatory effects are mediated by the modulation of Ca 2 + signalling in smooth muscle cells, but the mechanisms, especially with respect to the type of Ca channels involved, remain uncertain (126)(127)(128)(129) .…”

Effect of Long-Term Diabetes on Serotonin-Mediated Contraction in Carotid Arteries from Streptozotocin-Induced Diabetic Male and Female Rats

“…[25][26][27] Blood glucose was measured by a glucose meter (OneTouch Ultra, LifeScan, Johnson & Johnson Company, Milpitas, CA, U.S.A.). Plasma lipid parameters and plasma insulin were measured using commercially available kits (Wako Pure Chemical Industries, Ltd., Osaka, Japan and Shibayagi, Gunma, Japan, respectively).…”

Effect of Short-term Polyphenol Treatment on Endothelial Dysfunction and Thromboxane A₂ Levels in Streptozotocin-Induced Diabetic Mice

“…[8][9][10][11][12][13][14][15][16]27,28) Plasma samples were stored at −20°C until analysis. Briefly, plasma glucose, cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, and serum non-esterified fatty acid (NEFA) levels were each determined with a commercially available enzyme kit (Wako Pure Chemical Industries, Ltd., Osaka, Japan).…”

“…The endothelium plays a central role in physiological maintenance of the vascular function by regulating vascular tone, leukocyte adhesion, and platelet activation, as a result of the release of vasoactive substances such as nitric oxide (NO), prostacyclin, and thromboxane A 2 (TXA 2 ). 1,[6][7][8][9][10][11][12][13][14][15][16] Several natural polyphenols have been evaluated for their ability to protect against endothelial dysfunction and, thus, for their effectiveness in preventing cardiovascular disease. 17) Indeed, we have also shown that long-term chlorogenic acid (CA) treatment (2 months) can normalize the impaired endothelium-dependent relaxation seen in diabetic rats.…”