Interference with PPARγ function in smooth muscle causes vascular dysfunction and hypertension
Interference with PPARγ function in smooth muscle causes vascular dysfunction and hypertension
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DOI：
10.1016/j.cmet.2007.12.008
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发表时间：
2008-03-01
期刊：
影响因子：
29
通讯作者：
Sigmund, Curt D.
中科院分区：
文献类型：
--
作者：
Halabi, Carmen M.;Beyer, Andreas M.;Sigmund, Curt D.
过氧化物酶体增殖物激活受体γ(PPARγ)是一种配体激活的转录因子，在新陈代谢中起关键作用。噻唑烷二酮是临床上用于治疗II型糖尿病的高亲和力PPAR伽马配体，据报道，它可以降低血压并提供其他心血管益处。PPARγ(PPARG)的一些突变会导致II型糖尿病和严重高血压。在这里，我们检验了一种假设，即血管肌肉中的PPAR伽马在调节血管张力和血压方面发挥作用。在平滑肌特异性启动子的控制下，表达PPARγ显性-负性突变的转基因小鼠表现出对一氧化氮的反应性丧失，主动脉收缩能力显著改变，大脑微循环肥大和向内重构，以及收缩期高血压。这些结果证实PPAR-γ在血管肌肉中是关键的，作为血管结构、血管功能和血压的调节器，潜在地解释了噻唑烷二酮类药物的一些心脏保护作用。
Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-activated transcription factor that plays a critical role in metabolism. Thiazolidinediones, high-affinity PPAR gamma ligands used clinically to treat type II diabetes, have been reported to lower blood pressure and provide other cardiovascular benefits. Some mutations in PPAR gamma (PPARG) cause type II diabetes and severe hypertension. Here we tested the hypothesis that PPAR gamma in vascular muscle plays a role in the regulation of vascular tone and blood pressure. Transgenic mice expressing dominant-negative mutations in PPAR gamma under the control of a smooth-muscle-specific promoter exhibit a loss of responsiveness to nitric oxide and striking alterations in contractility in the aorta, hypertrophy and inward remodeling in the cerebral microcirculation, and systolic hypertension. These results identify PPAR gamma as pivotal in vascular muscle as a regulator of vascular structure, vascular function, and blood pressure, potentially explaining some of the cardioprotective effects of thiazolidinediones.