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非诺贝特通过脂联素依赖途径促进缺血诱导的血管新生。

Fenofibrate promotes ischemia-induced revascularization through the adiponectin-dependent pathway.

机构信息

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

出版信息

Am J Physiol Endocrinol Metab. 2010 Oct;299(4):E560-6. doi: 10.1152/ajpendo.00284.2010. Epub 2010 Jul 27.

Abstract

Recent clinical trials demonstrated that PPARα agonist fenofibrate reduces cardiovascular events, including limb amputation in people with type 2 diabetes. Here, we investigated whether fenofibrate modulates the revascularization process in a mouse model of hindlimb ischemia. Treatment with fenofibrate led to acceleration of revascularization of ischemic hindlimb relative to the contralatereal limb in wild-type (WT) mice, as measured by laser Doppler blood flow and capillary density analyses. Treatment of WT mice with fenofibrate increased the serum levels of adiponectin, which has protective actions on the vasculature. Of importance, fenofibrate had no effects on the revascularization in ischemic limbs of adiponectin-deficient (APN-KO) mice. Fenofibrate stimulated the phosphorylation of AMPK and eNOS in the ischemic muscles in WT mice but not in APN-KO mice. AMPK inhibitor compound C suppressed fenofibrate-induced increase in limb perfusion and AMPK phosphorylation in ischemic muscle in WT mice without affecting adiponectin levels. NOS inhibitor l-NAME also blocked the increased blood flow of ischemic limbs in fenofibrate-treated WT mice. Our observations suggest that fenofibrate could promote revascularization in response to ischemia through adiponectin-dependent AMPK signaling.

摘要

最近的临床试验表明,过氧化物酶体增殖物激活受体α 激动剂非诺贝特可降低心血管事件的发生,包括 2 型糖尿病患者的肢体截肢。在这里,我们研究了非诺贝特是否可以调节小鼠后肢缺血模型中的再血管化过程。与野生型(WT)小鼠的对侧肢体相比,非诺贝特治疗导致缺血后肢的再血管化加速,这通过激光多普勒血流和毛细血管密度分析来衡量。用非诺贝特治疗 WT 小鼠增加了脂联素的血清水平,脂联素对血管具有保护作用。重要的是,非诺贝特对脂联素缺乏(APN-KO)小鼠缺血肢体的再血管化没有影响。非诺贝特刺激 WT 小鼠缺血肌肉中 AMPK 和 eNOS 的磷酸化,但在 APN-KO 小鼠中没有。AMPK 抑制剂化合物 C 抑制了 WT 小鼠缺血肌肉中非诺贝特诱导的肢体灌注增加和 AMPK 磷酸化,而不影响脂联素水平。NOS 抑制剂 l-NAME 也阻断了非诺贝特治疗的 WT 小鼠缺血肢体的血流量增加。我们的观察表明,非诺贝特可以通过脂联素依赖性 AMPK 信号通路促进缺血后的再血管化。

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