Two distinct dysfunctions in diabetic mouse mesenteric artery contraction are caused by changes in the Rho A-Rho kinase signaling pathway.
Two distinct dysfunctions in diabetic mouse mesenteric artery contraction are caused by changes in the Rho A-Rho kinase signaling pathway.
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DOI：
10.1016/j.ejphar.2012.03.022
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发表时间：
2012-05
影响因子：
5
通讯作者：
K. Nobe;T. Hashimoto;K. Honda
中科院分区：
文献类型：
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作者：
K. Nobe;T. Hashimoto;K. Honda
糖尿病并发症与小动脉功能障碍有关。本研究的目的是确定糖尿病小鼠和非糖尿病小鼠肠系膜动脉第二分支(肠系膜动脉-2)作为一种典型的小动脉的内皮细胞剥离收缩的差异。在16-22周龄的雄性2型糖尿病ob/ob小鼠和年龄匹配的对照(LEAN)小鼠中，评估了肠系膜动脉-2的收缩反应。在10μM苯肾上腺素作用下，瘦小鼠的收缩反应呈剂量依赖性(1126.8±28.6mN/mm组织；n=5)，而ob/ob小鼠的收缩反应显著减弱(10μM苯肾上腺素作用下为716.8±40.8mN/mm；n=5)。暴露于高糖(HG；是正常葡萄糖[NG]浓度的两倍)可增强Lean(1341.4±15.5mN/mm；n=5)苯肾上腺素诱导的收缩，但对ob/ob小鼠无影响。这些功能障碍不涉及α1受体敏化或蛋白激酶活性，尽管ob/ob小鼠的收缩钙敏感性降低。Rho激酶抑制剂Y27632在NG条件下抑制了Lean和ob/ob小鼠之间的差异，并伴随着Rho A的失活。在HG条件下，ob/ob小鼠的葡萄糖依赖的Rho A活性持续存在，而Rho激酶的表达减少。这些数据表明，在NG条件下，Rho A的失活降低了收缩能力，缺乏葡萄糖依赖性与Rho激酶表达减少有关。
Diabetic complications are associated with small artery dysfunctions. The objective of this study was to identify differences in endothelial cell-denuded mesenteric artery second branch (mesenteric artery-2) contraction, as a typical small artery, between diabetic and non-diabetic mice. Contractile responses in mesenteric artery-2 were assessed in male type 2 diabetic ob/ob mice aged 16–22weeks and in age-matched control (Lean) mice. Phenylephrine induced dose-dependent contractions in Lean mice (1126.8±28.6mN/mm tissue at 10μM phenylephrine; n=5), which were significantly reduced in ob/ob mice (716.8±40.8mN/mm at 10μM phenylephrine; n=5). Exposure to high glucose (HG; twice the normal glucose [NG] concentration) enhanced phenylephrine-induced contraction in Lean (1341.4±15.5mN/mm; n=5) but not in ob/ob mice. These dysfunctions did not involve α1-receptor sensitization or protein kinase activity, although the calcium sensitivity of contraction was decreased in ob/ob mice. The Rho kinase inhibitor Y27632 suppressed the difference between Lean and ob/ob mice under NG conditions, which was accompanied by Rho A inactivation. Under HG conditions, glucose-dependent Rho A activation persisted in ob/ob mice whereas Rho kinase expression was reduced. These data suggest that inactivation of Rho A reduced contractibility under NG conditions, and the lack of glucose dependency is associated with reduced Rho kinase expression.