Simvastatin stimulates VEGF release via p44/p42 MAP kinase in vascular smooth muscle cells.
Simvastatin stimulates VEGF release via p44/p42 MAP kinase in vascular smooth muscle cells.
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DOI：
10.1016/s0006-291x(02)03014-0
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发表时间：
2003-01
影响因子：
3.1
通讯作者：
M. Takenaka;K. Hirade;K. Tanabe;Shigeru Akamatsu;S. Dohi;H. Matsuno;O. Kozawa
中科院分区：
文献类型：
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作者：
M. Takenaka;K. Hirade;K. Tanabe;Shigeru Akamatsu;S. Dohi;H. Matsuno;O. Kozawa
已显示3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类）调节血管平滑肌细胞功能。在本研究中，我们研究了辛伐他汀对血管内皮生长因子（VEGF）释放的影响，并在大鼠主动脉平滑肌细胞系，A10细胞的潜在机制。辛伐他汀可增加大鼠体内血浆VEGF水平。在培养的细胞中，辛伐他汀以剂量依赖性方式显著刺激VEGF释放。辛伐他汀诱导p44/p42 MAP激酶磷酸化，但不诱导p38 MAP激酶或SAPK（应激活化蛋白激酶）/JNK（c-Jun N-末端激酶）磷酸化。PD 98059和U-0126是激活p44/p42 MAP激酶的上游激酶的抑制剂，以剂量依赖性方式显著减少辛伐他汀诱导的VEGF释放。PD 98059或U-0126可降低辛伐他汀诱导的p44/p42 MAP激酶磷酸化。此外，推注PD 98059确实抑制了体内大鼠血浆中辛伐他汀增加的VEGF水平。这些结果有力地表明，p44/p42 MAP激酶至少部分地在辛伐他汀刺激血管平滑肌细胞VEGF释放中起作用。
It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) modulate vascular smooth muscle cell functions. In the present study, we investigated the effect of simvastatin on vascular endothelial growth factor (VEGF) release, and the underlying mechanism, in a rat aortic smooth muscle cell line, A10 cells. Administration of simvastatin increased the VEGF level in rat plasma in vivo. In cultured cells, simvastatin significantly stimulated VEGF release in a dose-dependent manner. Simvastatin induced the phosphorylation of p44/p42 MAP kinase but not p38 MAP kinase or SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase). PD98059 and U-0126, inhibitors of the upstream kinase that activates p44/p42 MAP kinase, significantly reduced the simvastatin-induced VEGF release in a dose-dependent manner. The phosphorylation of p44/p42 MAP kinase induced by simvastatin was reduced by PD98059 or U-0126. Moreover, a bolus injection of PD98059 truly suppressed the simvastatin-increased VEGF level in rat plasma in vivo. These results strongly suggest that p44/p42 MAP kinase plays a role at least partly in the simvastatin-stimulated VEGF release in vascular smooth muscle cells.