Involvement of NO and MEK/ERK pathway in enhancement of endothelin-1-induced mesenteric artery contraction in later-stage type 2 diabetic Goto-Kakizaki rat
Involvement of NO and MEK/ERK pathway in enhancement of endothelin-1-induced mesenteric artery contraction in later-stage type 2 diabetic Goto-Kakizaki rat
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DOI：
10.1152/ajpheart.00043.2009
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发表时间：
2009-05-01
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;Ishida, Keiko;Kamata, Katsuo
Matsumoto T, Ishida K, Nakayama N, Kobayashi T, Kamata K. NO和MEK/ERK通路参与内皮素-1诱导的晚期2型糖尿病大鼠肠系膜动脉收缩。[J]中国生物医学工程杂志，2009。首次发表于2009年3月13日；doi: 10.1152 / ajpheart.00043.2009。-内皮素(ET)-1可能在糖尿病血管并发症中起关键作用。然而，在2型糖尿病的慢性阶段，血管对ET-1的反应性没有异常。我们的目的是寻找ET受体（ETA和ETB）在2型糖尿病Goto-Kakizaki （GK）大鼠肠系膜动脉中的异常作用，并确定所涉及的分子机制。我们利用晚期（32-38周龄）个体的肠系膜动脉，比较了选择性ETB受体激动剂IRL1620在GK大鼠和对照Wistar大鼠之间引起的et -1诱导的收缩和舒张。测定肠系膜动脉ERK活性、ET受体和MEK蛋白表达。在GK大鼠中（与年龄匹配的Wistar大鼠相比），我们发现如下。1) ETA拮抗剂BQ-123对et -1诱导的收缩作用更大，但BQ-788对其没有抑制作用。在控制中，BQ-788增强了这种收缩。2) IRL1620诱导的松弛和一氧化氮（NO）生成均减少。3) n - g -硝基- l -精氨酸（L-NNA； NO合成酶抑制剂）增强et -1诱导的收缩，硝普钠（NO供体）抑制et -1诱导的收缩。4) MEK/ERK通路抑制剂（PD-98059或U0126）可降低et -1诱导的增强收缩。5) et -1刺激的ERK活化增加，ETA和MEK1/2蛋白表达增加。6)肠系膜ET-1含量升高。这些结果表明，ETA的上调，etb介导的NO信号的缺陷，以及MEK/ERK通路的激活共同代表了本研究中检测的介导ET-1高反应性的可能机制。
Matsumoto T, Ishida K, Nakayama N, Kobayashi T, Kamata K. Involvement of NO and MEK/ERK pathway in enhancement of endothelin-1-induced mesenteric artery contraction in later-stage type 2 diabetic Goto-Kakizaki rat. Am J Physiol Heart Circ Physiol 296: H1388-H1397, 2009. First published March 13, 2009; doi:10.1152/ajpheart.00043.2009.-Endothelin (ET)-1 is a likely candidate for a key role in diabetic vascular complications. However, no abnormalities in the vascular responsiveness to ET-1 have been identified in the chronic stage of type 2 diabetes. Our goal was to look for abnormalities in the roles played by ET receptors (ETA and ETB) in the mesenteric artery of the type 2 diabetic Goto-Kakizaki (GK) rat and to identify the molecular mechanisms involved. Using mesenteric arteries from later-stage (32-38 wk old) individuals, we compared the ET-1-induced contraction and the relaxation induced by the selective ETB receptor agonist IRL1620 between GK rats and control Wistar rats. Mesenteric artery ERK activity and the protein expressions for ET receptors and MEK were also measured. In GK rats (vs. age-matched Wistar rats), we found as follows. 1) The ET-1-induced contraction was greater and was attenuated by BQ-123 (ETA antagonist) but not by BQ-788 (ETB antagonist). In the controls, BQ-788 augmented this contraction. 2) Both the relaxation and nitric oxide (NO) production induced by IRL1620 were reduced. 3) ET-1-induced contraction was enhanced by N-G-nitro-L-arginine (L-NNA; NO synthase inhibitor) but suppressed by sodium nitroprusside (NO donor). 4) The enhanced ET-1-induced contraction was reduced by MEK/ERK pathway inhibitors (PD-98059 or U0126). 5) ET-1-stimulated ERK activation was increased, as were the ETA and MEK1/2 protein expressions. 6) Mesenteric ET-1 content was increased. These results suggest that upregulation of ETA, a defect in ETB-mediated NO signaling, and activation of the MEK/ERK pathway together represent a likely mechanism mediating the hyperreactivity to ET-1 examined in this study.