Matsumoto Takayuki, Nakayama Naoaki, Ishida Keiko, Kobayashi Tsuneo, Kamata Katsuo
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
J Pharmacol Exp Ther. 2009 Apr;329(1):324-34. doi: 10.1124/jpet.108.148718. Epub 2009 Jan 22.
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.
越来越多的证据表明，饮食中摄入n-3多不饱和脂肪酸（PUFAs）与几种涉及内皮功能障碍的心血管疾病发病率降低有关。然而，其分子机制仍不清楚。我们之前报道，2型糖尿病大冢长-艾-托卡ushima肥胖（OLETF）大鼠的肠系膜动脉表现出内皮功能障碍，导致内皮源性血管舒张剂[即一氧化氮（NO）和内皮源性超极化因子（EDHF）]与血管收缩剂[内皮源性收缩因子（EDCFs）][即环氧化酶（COX）衍生的前列腺素]之间失衡（《美国生理学杂志：心脏和循环生理学》293：H1480-H1490，2007）。我们假设用二十碳五烯酸（EPA）（一种主要的n-3多不饱和脂肪酸）治疗OLETF大鼠可能通过纠正这种失衡来改善内皮功能障碍。在OLETF大鼠中[与年龄匹配的对照大冢长-艾-托卡ushima（LETO）大鼠相比]：1）乙酰胆碱（ACh）诱导的（内皮依赖性）舒张受损，2）NO和EDHF介导的舒张及亚硝酸盐生成减少，3）ACh诱导的EDCF介导的收缩、前列腺素生成以及COX-1和COX-2的蛋白表达均增加。当OLETF大鼠长期接受慢性EPA治疗（口服300 mg/kg/天，持续4周）时，其分离的肠系膜动脉表现出：1）ACh诱导的NO和EDHF介导的舒张以及COX介导的收缩得到改善，2）EDCF和花生四烯酸诱导的收缩减少，3）NO代谢正常化，4）前列腺素生成受到抑制，5）COX-2表达降低，6）磷酸化细胞外信号调节激酶（ERK）表达降低。此外，EPA治疗降低了分离的OLETF主动脉中ERK2和核因子（NF）-κB的活性。我们提出，EPA通过纠正内皮源性因子之间的失衡来改善OLETF大鼠的内皮功能障碍，至少部分是通过抑制ERK、降低NF-κB激活以及减少COX-2表达来实现的。
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