G protein-coupled receptor kinase-5 attenuates atherosclerosis by regulating receptor tyrosine kinases and 7-transmembrane receptors.
G protein-coupled receptor kinase-5 attenuates atherosclerosis by regulating receptor tyrosine kinases and 7-transmembrane receptors.
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DOI：
10.1161/atvbaha.111.239608
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Freedman NJ
中科院分区：
文献类型：
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作者：
Wu JH;Zhang L;Fanaroff AC;Cai X;Sharma KC;Brian L;Exum ST;Shenoy SK;Peppel K;Freedman NJ
G蛋白偶联受体激酶5(GRK5)是一种广泛表达的丝氨酸/苏氨酸受体，调节多种致动脉粥样硬化受体，可能激活或抑制核因子κB。本研究试图确定GRK5是否影响动脉粥样硬化以及通过何种机制影响动脉粥样硬化。GRK5−/−/apoE−/−小鼠出现的动脉粥样硬化程度比apoe−/−小鼠高50%，并且在动脉粥样硬化病变中表现出更多的巨噬细胞和平滑肌细胞(SMC)的增殖。在APOE−/−小鼠中，来自GRK5−/−小鼠的颈动脉间置移植物比来自WT小鼠的移植物显示出更多的细胞黏附分子上调，随后出现更多的动脉粥样硬化。通过比较GRK5和WT细胞，我们发现GRK5通过增加泛素化/降解来减敏两个关键的致动脉粥样硬化受体酪氨酸激酶：SMC中的PDGFR−/−(PDGFRβ)和巨噬细胞中的集落刺激因子-1受体(CSF1R)，通过减少CSF1诱导的酪氨酸磷酸化。单核细胞的GRK5活性也减少了MCP-1的7-跨膜受体(CCR2)促进的迁移。GRK5可降低血管内皮细胞和血管内皮细胞中依赖于NFκB的基因表达，但对巨噬细胞中的NFκB活性无明显影响。GRK5通过多种细胞类型的特异性机制减轻动脉粥样硬化，包括降低平滑肌细胞和内皮细胞的NFCSFRB活性，以及通过单核细胞κ-1R、巨噬细胞CSF1R和SMC PDGFRβ脱敏受体特异性信号。
G protein-coupled receptor kinase-5 (GRK5) is a widely expressed Ser/Thr kinase that regulates several atherogenic receptors, and may activate or inhibit NFκB. This study sought to determine whether and by what mechanisms GRK5 affects atherosclerosis. Grk5−/−/Apoe−/− mice developed 50% greater aortic atherosclerosis than Apoe−/− mice, and demonstrated greater proliferation of macrophages and smooth muscle cells (SMCs) in atherosclerotic lesions. In Apoe−/− mice, carotid interposition grafts from Grk5−/− mice demonstrated greater up-regulation of cell adhesion molecules than grafts from WT mice, and subsequently more atherosclerosis. By comparing Grk5−/− with WT cells, we found that GRK5 desensitized two key atherogenic receptor tyrosine kinases: the PDGF receptor-β (PDGFRβ) in SMCs, by augmenting ubiquitination/degradation; the colony stimulating factor-1 receptor (CSF-1R) in macrophages, by reducing CSF-1-induced tyrosyl phosphorylation. GRK5 activity in monocytes also reduced migration promoted by the 7-transmembrane receptor for MCP-1 (CCR2). Whereas GRK5 diminished NFκB-dependent gene expression in SMCs and endothelial cells, it had no effect on NFκB activity in macrophages. GRK5 attenuates atherosclerosis through multiple cell type-specific mechanisms, including reduction of SMC and endothelial cell NFκB activity, and desensitization of receptor-specific signaling through the monocyte CCR2, macrophage CSF-1R, and the SMC PDGFRβ.