Central role of the MAPK pathway in ang II-mediated DNA synthesis and migration in rat vascular smooth muscle cells.
Central role of the MAPK pathway in ang II-mediated DNA synthesis and migration in rat vascular smooth muscle cells.
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DOI：
10.1161/01.atv.19.1.73
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
X. Xi;K. Graf;S. Goetze;E. Fleck;W. Hsueh;R. Law
中科院分区：
文献类型：
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作者：
X. Xi;K. Graf;S. Goetze;E. Fleck;W. Hsueh;R. Law
血管紧张素II （angii）促进血管平滑肌细胞（VSMC）的生长和迁移，但介导这些VSMC行为的信号通路对再狭窄和动脉粥样硬化至关重要。本研究的目的是确定丝裂原活化蛋白激酶（MAPK）在Ang ii诱导的VSMCs中DNA合成、迁移和c-fos诱导中的作用。PD 98059是一种合成的MAPK激酶抑制剂，或用于消耗细胞外信号调节激酶（ERK）1和ERK2 MAPKs的反义寡脱氧核苷酸（ODNs），用于抑制MAPK信号传导。PD 98059在30微mol/L浓度下使Ang ii诱导的MAPK活性降低69% （P<0.01）。在这些条件下，Ang ii诱导的DNA合成被完全抑制（P<0.01）， Ang ii引导的迁移被减弱76% （P<0.05）。相比之下，Angⅱ对c-fos的诱导仅部分抑制（抑制58%，P<0.01）。针对大鼠ERK1和ERK2 MAPK mrna起始位点的反义ODNs使相应的蛋白水平降低63% (P<0.01)，并完全抑制angii（1微mol/L）或10%血清中MAPK的激活。反义odn（0.4微mol/L）完全抑制Angⅱ诱导的DNA合成（P<0.01），减少47%的迁移（P<0.01），减少40%的c-fos诱导（P<0.01）。Ang II型1 （AT1）受体阻滞剂厄贝沙坦完全阻断了VSMCs中Ang II的DNA合成、迁移、MAPK激活和c-fos诱导。这些结果表明，MAPK的激活在Ang ii定向迁移和通过AT1受体的DNA合成中起着至关重要的作用。相反，Ang II介导的c-fos诱导和迁移仅被反义odn或PD 98059部分抑制，这表明除了MAPK途径外，Ang II的这些作用可能还参与了其他途径。我们得出结论，MAPK是angii介导的VSMCs迁移和生长的关键调控因子。Ang ii诱导的DNA合成表现出比Ang ii引导的迁移或c-fos诱导更强的MAPK依赖性。
Angiotensin II (Ang II) promotes vascular smooth muscle cell (VSMC) growth and migration, but the signaling pathways mediating these VSMC behaviors critical to restenosis and atherosclerosis are not completely known. The purpose of the present investigation was to define the role of mitogen-activated protein kinase (MAPK) in Ang II-induced DNA synthesis, migration, and c-fos induction in VSMCs. PD 98059, a synthetic inhibitor of MAPK kinase, or antisense oligodeoxynucleotides (ODNs) to deplete extracellular signal-regulated kinase (ERK)1 and ERK2 MAPKs, were used to inhibit MAPK signaling. PD 98059 at 30 micromol/L reduced Ang II-induced MAPK activity by 69% (P<0.01). Under these conditions, Ang II-induced DNA synthesis was completely inhibited (P<0.01), and Ang II-directed migration was attenuated by 76% (P<0.05). In contrast, induction of c-fos by Ang II was only partially suppressed (58% inhibition, P<0.01). Antisense ODNs against the initiation site of rat ERK1 and ERK2 MAPK mRNAs reduced corresponding protein levels by 63% (P<0.01) and completely inhibited MAPK activation by either Ang II (1 micromol/L) or 10% serum. Antisense ODNs (0.4 micromol/L) completely inhibited Ang II-induced DNA synthesis (P<0.01), decreased migration by 47% (P<0.01), and reduced c-fos induction by 40% (P<0.01 versus control ODN-transfected VSMCs). The Ang II type 1 (AT1)-receptor blocker irbesartan completely blocked DNA synthesis, migration, MAPK activation, and c-fos induction by Ang II in VSMCs. These results demonstrate that activation of MAPK plays a crucial role in Ang II-directed migration and DNA synthesis through the AT1 receptor. In contrast, Ang II-mediated c-fos induction and migration were only partially inhibited by either antisense ODNs or PD 98059, suggesting that other pathways in addition to the MAPK pathway may be involved in these actions of Ang II. We conclude that MAPK is a critical regulatory factor for Ang II-mediated migration and growth in VSMCs. Ang II-induced DNA synthesis showed a stronger MAPK dependence than did Ang II-directed migration or c-fos induction.