Metformin normalizes endothelial function by suppressing vasoconstrictor prostanoids in mesenteric arteries from OLETF rats, a model of type 2 diabetes
Metformin normalizes endothelial function by suppressing vasoconstrictor prostanoids in mesenteric arteries from OLETF rats, a model of type 2 diabetes
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DOI：
10.1152/ajpheart.00486.2008
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发表时间：
2008-09-01
影响因子：
4.8
通讯作者：
Kamata, Katsuo
中科院分区：
文献类型：
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作者：
Matsumoto, Takayuki;Noguchi, Eri;Kamata, Katsuo
我们以前报道过，在老年大冢Long-Evans德岛脂肪（OLETF）大鼠（2型糖尿病模型）的肠系膜动脉中，内皮衍生超极化因子（EDHF）型舒张受损，而内皮衍生收缩因子（EDCF）介导的收缩增强（松本T，Kakami M，Noguchi E，小林T，Kamata K. Am J Physiol Heart Circ Physiol 293：H1480-H1490，2007）。在这里，我们研究了二甲双胍急性和/或慢性治疗是否可以改善从OLETF大鼠分离的肠系膜动脉中上述内皮衍生因子的作用之间的这种不平衡。在OLETF肠系膜动脉的急性研究中，ACh诱导的舒张受损，并且在高ACh浓度下舒张变得更弱。二甲双胍和5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷[AICAR，一种AMP激活蛋白激酶（AMPK）激活剂，也可被二甲双胍激活] 1）降低了高ACh浓度下舒张逆转的趋势，2）抑制ACh诱导的EDCF介导的收缩和ACh刺激的前列腺素类（血栓烷A（2）和PGE（2））的产生。在对长期给药动物的OLETF动脉进行的研究中，二甲双胍给药（300 mg.kg（-1）.day（-1），持续4周）1）改善了ACh诱导的一氧化氮或EDHF介导的舒张和环氧合酶（考克斯）介导的收缩，2）减少了EDCF介导的收缩，3）抑制了前列腺素类的产生，4）减少了超氧化物的产生。二甲双胍不改变内皮型一氧化氮合酶（eNOS）、磷酸型eNOS（Ser 1177）或考克斯-1的蛋白表达，但增加考克斯-2蛋白。这些结果表明，二甲双胍通过抑制血管收缩剂前列腺素类和减少氧化应激改善OLETF肠系膜动脉的内皮功能。我们的数据表明，在本文研究的时间范围内，二甲双胍通过这种直接机制改善内皮功能，而不是通过改善代谢异常。
We previously reported that in mesenteric arteries from aged Otsuka Long-Evans Tokushima fatty (OLETF) rats (a type 2 diabetes model) endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired while endothelium-derived contracting factor (EDCF)-mediated contraction is enhanced (Matsumoto T, Kakami M, Noguchi E, Kobayashi T, Kamata K. Am J Physiol Heart Circ Physiol 293: H1480-H1490, 2007). Here we investigated whether acute and/or chronic treatment with metformin might improve this imbalance between the effects of the above endothelium-derived factors in mesenteric arteries isolated from OLETF rats. In acute studies on OLETF mesenteric arteries, ACh-induced relaxation was impaired and the relaxation became weaker at high ACh concentrations. Both metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside [AICAR, an AMP-activated protein kinase (AMPK) activator that is also activated by metformin] 1) diminished the tendency for the relaxation to reverse at high ACh concentrations and 2) suppressed both ACh-induced EDCF-mediated contraction and ACh-stimulated production of prostanoids (thromboxane A(2) and PGE(2)). In studies on OLETF arteries from chronically treated animals, metformin treatment (300 mg.kg(-1).day(-1) for 4 wk) 1) improved ACh-induced nitric oxide-or EDHF-mediated relaxation and cyclooxygenase (COX)-mediated contraction, 2) reduced EDCF-mediated contraction, 3) suppressed production of prostanoids, and 4) reduced superoxide generation. Metformin did not alter the protein expressions of endothelial nitric oxide synthase (eNOS), phospho-eNOS (Ser1177), or COX-1, but it increased COX-2 protein. These results suggest that metformin improves endothelial functions in OLETF mesenteric arteries by suppressing vasoconstrictor prostanoids and by reducing oxidative stress. Our data suggest that within the timescale studied here, metformin improves endothelial function through this direct mechanism, rather than by improving metabolic abnormalities.