Bcr kinase activation by angiotensin II inhibits peroxisome-proliferator-activated receptor gamma transcriptional activity in vascular smooth muscle cells.
Bcr kinase activation by angiotensin II inhibits peroxisome-proliferator-activated receptor gamma transcriptional activity in vascular smooth muscle cells.
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DOI：
10.1161/circresaha.108.188409
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发表时间：
2009-01-02
影响因子：
20.1
通讯作者：
Abe J
中科院分区：
文献类型：
--
作者：
Alexis JD;Wang N;Che W;Lerner-Marmarosh N;Sahni A;Korshunov VA;Zou Y;Ding B;Yan C;Berk BC;Abe J
Bcr是由PDGF激活的丝氨酸/苏氨酸激酶，在血管损伤后的新生内膜中高度表达。在这里，我们证明，Bcr是血管紧张素II（AngII）和PDGF介导的血管平滑肌细胞（VSMC）炎症反应的重要介质。在可能调节AngII介导的炎症反应的转录因子中，我们发现配体介导的PPARγ转录活性被AngII显著降低。AngII增加Bcr表达和激酶活性。过表达Bcr可显著抑制PPARγ活性。相反，使用Bcr siRNA和Bcr的显性负性形式（DN-Bcr）敲低Bcr可显著逆转AngII介导的PPARγ活性抑制，表明Bcr在AngII介导的PPARγ活性抑制中起关键作用。点突变和体外激酶分析表明，PPARγ被Bcr磷酸化的丝氨酸82。WT-Bcr激酶的过表达并不抑制配体介导的PPARγ 1 S82 A突变体的转录活性，表明Bcr通过S82磷酸化调节PPARγ活性。DN-Bcr和Bcr siRNA可抑制Ang II介导的NF-κB活化。DN-PPARγ可逆转DN-Bcr对NF-κB活化的抑制作用，提示其位于Bcr的下游。与野生型小鼠相比，Bcr基因敲除小鼠低流量颈动脉内膜增殖减少，表明Bcr激酶在体内VSMC增殖中起关键作用，至少部分通过调节PPARγ/NF-κB转录活性。
Bcr is a serine/threonine kinase activated by PDGF that is highly expressed in the neointima after vascular injury. Here, we demonstrate that Bcr is an important mediator of angiotensin II (AngII) and PDGF mediated inflammatory responses in vascular smooth muscle cells (VSMC). Among transcription factors that might regulate AngII-mediated inflammatory responses we found that ligand-mediated PPARγ transcriptional activity was significantly decreased by AngII. AngII increased Bcr expression and kinase activity. Overexpression of Bcr significantly inhibited PPARγ activity. In contrast, knockdown of Bcr using Bcr siRNA and a dominant negative form of Bcr (DN-Bcr) reversed AngII-mediated inhibition of PPARγ activity significantly, suggesting the critical role of Bcr in AngII-mediated inhibition of PPARγ activity. Point-mutation and in vitro kinase analysis showed that PPARγ was phosphorylated by Bcr at serine 82. Overexpression of WT-Bcr kinase did not inhibit ligand-mediated PPARγ 1 S82A mutant transcriptional activity, indicating that Bcr regulates PPARγ activity via S82 phosphorylation. DN-Bcr and Bcr siRNA inhibited AngII-mediated NF-κB activation in VSMC. DN-PPARγ reversed DN-Bcr mediated inhibition of NF-κB activation, suggesting that PPARγ is downstream from Bcr. Intimal proliferation in low flow carotid arteries was decreased in Bcr knockout mice compared with wild type mice suggesting the critical role of Bcr kinase in VSMC proliferation in vivo, at least in part, via regulating PPARγ/NF-κB transcriptional activity.