Angiotensin II stimulates platelet-derived growth factor-B chain expression in newborn rat vascular smooth muscle cells and neointimal cells through Ras, extracellular signal-regulated protein kinase, and c-Jun N-terminal protein kinase mechanisms
Angiotensin II stimulates platelet-derived growth factor-B chain expression in newborn rat vascular smooth muscle cells and neointimal cells through Ras, extracellular signal-regulated protein kinase, and c-Jun N-terminal protein kinase mechanisms
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DOI：
10.1161/01.res.85.7.565
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发表时间：
1999-10-01
影响因子：
20.1
通讯作者：
Takuwa, Y
中科院分区：
文献类型：
--
作者：
Deguchi, J;Makuuchi, M;Takuwa, Y
血小板衍生生长因子(PDGFs)参与了血管增生性疾病的发病机制。血管平滑肌细胞(VSMCs)是增生性皮损中产生PDGF-B链的细胞类型之一，但对这些细胞中PDGF-B链产生的调控机制尚不清楚。在本研究中，我们证明了血管紧张素II(Ang II)可通过AT(1)显著刺激培养的新生大鼠中膜VSMCs和新生血管内膜VSMCs的PDGF-B链mRNA表达，但对成年大鼠VSMCs无此作用。Ang II也与血管成形术后血管狭窄和动脉粥样硬化有关。在新生大鼠VSMCs中，Ang II激活细胞外信号调节蛋白激酶(ERK)、c-jun氨基末端蛋白激酶(JNK)和p38丝裂原活化蛋白激酶。丝裂原活化蛋白/ERK(MEK)抑制剂PD98059，而不是p38抑制剂SB203580，可阻断Ang II诱导的PDGF-B mRNA表达。使用PDGF-B启动子-荧光素酶基因报告构建的瞬时转染分析表明，Ang II诱导PDGF-B链基因的转录激活，这种转录激活被显性的ERK或JNK表达取消，而不是p38的表达。显性负性RAS的表达取消了血管紧张素Ⅱ对ERK活性和PDGF-B基因表达的刺激作用。与新生大鼠VSMCs相比，成年大鼠VSMCs中Ang II可激活ERK和JNK，但对参与PDGF-B链基因表达的转录因子Egr-1的诱导作用较弱。提示Ang II通过Ras-ERK和JNK途径激活VSMC中PDGF-B链基因的表达。
Platelet-derived growth factors (PDGFs) have been implicated in the pathogenesis of vascular proliferative disorders. Vascular smooth muscle cells (VSMCs) are one of the cell types that produce PDGF-B chain in proliferative lesions, although the mechanism of regulation of PDGF-B chain production in these cells is not well understood. In the present study, we demonstrate that angiotensin II (Ang II), which is also implicated in vascular stenosis after angioplasty and atherosclerosis, markedly stimulates PDGF-B chain mRNA expression in cultured newborn rat medial VSMCs and neointimal VSMCs via an AT(1), but not in adult rat VSMCs. In newborn rat VSMCs, Ang II activates extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal protein kinase (JNK), and p38 mitogen-activated protein kinase. The mitogen-activated protein/ERK (MEK) inhibitor PD98059, but not the p38 inhibitor SB203580, abrogates Ang II-induced PDGF-B mRNA expression. Transient transfection analysis using a PDGF-B promoter-luciferase gene reporter construct reveals that Ang II induces transcriptional activation of PDGF-B chain gene, which is abolished by the expression of a dominant negative form of either ERK or JNK, but not of p38. The expression of a dominant negative form of Ras abolishes the stimulatory effects of Ang Il on ERK activity and PDGF-B mRNA expression. In adult rat VSMCs, Ang II activates ERK and JNK, but weakly induces Egr-1, a transcription factor implicated in PDGF-B chain gene expression, compared with newborn VSMCs. These data indicate that Ang II activates PDGF-B chain gene expression in VSMCs through mechanisms involving Ras-ERK and JNK.