Regulation of SM22α expression by arginine vasopressin and PDGF-BB in vascular smooth muscle cells
Regulation of SM22α expression by arginine vasopressin and PDGF-BB in vascular smooth muscle cells
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DOI：
10.1152/ajpheart.00306.2003
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发表时间：
2003-10-01
影响因子：
4.8
通讯作者：
Nemenoff, RA
中科院分区：
文献类型：
--
作者：
Kaplan-Albuquerque, N;Garat, C;Nemenoff, RA
血管平滑肌细胞（VSMC）在体内和体外经历表型调节。这个过程涉及多个SM特异性基因表达的协调变化。在培养的VSMC中，精氨酸加压素（AVP）增加和PDGF减少SM α-肌动蛋白（SMA）的表达，SM α-肌动蛋白是SM细胞（SMC）的最早标志物。然而，目前尚不清楚这些药物是否以类似的方式调节其他SM基因。在发育过程中，SM 22 α似乎继发于SMA，也是SMC的标志物。本研究检测了AVP和PDGF对培养的VSMC中SM 22 α表达的调节作用。AVP可使SM 22 α mRNA和蛋白水平升高，PDGF可抑制SM 22 α mRNA和蛋白水平的升高。与这些变化一致，AVP增加SM 22 α启动子活性，而PDGF抑制基础启动子活性并阻断AVP诱导的增加。JNK和p38 MAPK通路的激活对于AVP介导的SM 22 α启动子的诱导是必需的。组成型活性Ras的表达对SM 22 α启动子活性产生与PDGF相似的抑制作用。从PDGF/Ras活化传递的信号涉及Raf或竞争该位点的蛋白质、Ral-GDS和磷脂酰肌醇3-激酶活化。Trunchman分析表明，启动子中的三个CArG盒的近端位置足以刺激AVP。CArG盒中的突变降低了基础和AVP刺激的启动子活性，而不影响PDGF抑制。血清反应因子的过表达增强了基础启动子活性和AVP刺激的启动子活性，但对PDGF-BB诱导的抑制没有影响。这些数据表明，AVP和PDGF启动特定的信号传导途径，控制多个SM基因的表达，导致表型调节。
Vascular smooth muscle (SM) cells (VSMC) undergo phenotypic modulation in vivo and in vitro. This process involves coordinated changes in expression of multiple SM-specific genes. In cultured VSMC, arginine vasopressin (AVP) increases and PDGF decreases expression of SM alpha-actin (SMA), the earliest marker of SM cells (SMC). However, it is unknown whether these agents regulate other SM genes in a similar fashion. SM22alpha appears secondary to SMA during development and is also a marker for SMC. This study examined the regulation of SM22alpha expression by AVP and PDGF in cultured VSMC. Levels of SM22alpha mRNA and protein were increased by AVP and suppressed by PDGF. Consistent with these changes, AVP increased SM22alpha promoter activity, whereas PDGF inhibited basal promoter activity and blocked AVP-induced increase. Activation of both JNK and p38 MAPK pathways was necessary for AVP-mediated induction of SM22alpha promoter. Expression of constitutively active Ras produced similar suppressions on SM22alpha promoter activity as PDGF. Signaling relayed from PDGF/Ras activation involved Raf, or a protein that competes for this site, Ral-GDS, and phosphatidylinositol 3-kinase activation. Truncational analysis showed that the proximal location of three CArG boxes in the promoter was sufficient for AVP stimulation. Mutations in this CArG box reduced basal and AVP-stimulated promoter activity without effecting PDGF suppression. Overexpression of serum response factor enhanced basal and AVP-stimulated promoter activity but had no effect on PDGF-BB-induced suppression. These data indicate that AVP and PDGF initiate specific signaling pathways that control expression of multiple SM genes leading to phenotypic modulation.