Angiotensin II induction of PDGF-C expression is mediated by AT1 receptor-dependent Egr-1 transactivation.
Angiotensin II induction of PDGF-C expression is mediated by AT1 receptor-dependent Egr-1 transactivation.
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DOI：
10.1093/nar/gkm923
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发表时间：
2008-04
影响因子：
14.9
通讯作者：
Khachigian LM
中科院分区：
文献类型：
--
作者：
Sanchez-Guerrero E;Midgley VC;Khachigian LM
血小板源性生长因子（PDGFs）是一个由4个配体基因（A-、B-、C-、D-链）组成的有丝分裂原和趋化因子家族，参与动脉粥样硬化、纤维化和肿瘤发生等多种生理和病理生理过程。我们对调节PDGF-C转录的分子机制的理解仍然不完整。瞬时转染分析，常规和定量实时PCR揭示了PDGF-C的转录和mRNA表达的诱导平滑肌细胞（SMC）暴露于肽激素血管紧张素（ATII），诱导Egr-1。在PDGF-C启动子近端区域中富含G + C的元件的占据不受ATII的影响。相反，我们发现，使用细胞核提取物和重组蛋白与EMSA和ChIP分析，存在第二个Egr-1结合元件位于上游500 bp。ATII对PDGF-C转录的诱导由血管紧张素1型受体（AT 1 R）介导，Egr-1通过该上游元件激活。靶向Egr-1的DNAzyme ED 5阻断ATII诱导的PDGF-C表达。此外，暴露于ATII后增加的PDGF-C表达取决于SMC的分化状态。这项研究表明，这种新的ATII-AT 1 R-Egr-1-PDGF-C轴存在于新生儿来源的SMC中，但不在成人SMC中，其中ATII诱导Egr-1而不是PDGF-C。
Platelet-derived growth factors are a family of mitogens and chemoattractants comprising of four ligand genes (A-, B-, C-, D-chains) implicated in many physiologic and pathophysiologic processes, including atherosclerosis, fibrosis and tumorigenesis. Our understanding of the molecular mechanisms, which regulate PDGF-C transcription remains incomplete. Transient transfection analysis, conventional and quantitative real-time PCR revealed the induction of PDGF-C transcription and mRNA expression in smooth muscle cells (SMCs) exposed to the peptide hormone angiotensin (ATII), which induces Egr-1. Occupancy of a G + C-rich element in the proximal region of the PDGF-C promoter was unaffected by ATII. Instead we discovered, using both nuclear extracts and recombinant proteins with EMSA and ChIP analyses, the existence of a second Egr-1-binding element located 500 bp upstream. ATII induction of PDGF-C transcription is mediated by the angiotensin type 1 receptor (AT1R) and Egr-1 activation through this upstream element. DNAzyme ED5 targeting Egr-1 blocked ATII-inducible PDGF-C expression. Moreover, increased PDGF-C expression after exposure to ATII depends upon the differentiation state of the SMCs. This study demonstrates the existence of this novel ATII-AT1R-Egr-1-PDGF-C axis in SMCs of neonatal origin, but not in adult SMCs, where ATII induces Egr-1 but not PDGF-C.
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DOI：
10.1073/pnas.0409722102
发表时间：
2005-03-01
影响因子：
11.1
作者：
Campbell, JS;Hughes, SD;Fausto, N
通讯作者：
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影响因子：
30.8
作者：
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影响因子：
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作者：
Khachigian, LM
通讯作者：
Khachigian, LM
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影响因子：
14.9
作者：
通讯作者：
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影响因子：
20.1
作者：
Deguchi, J;Makuuchi, M;Takuwa, Y
通讯作者：
Takuwa, Y