The calcium channel blocker amlodipine exerts its anti¬proliferative action via p21(Waf1/Cip1) gene activation
The calcium channel blocker amlodipine exerts its anti¬proliferative action via p21(Waf1/Cip1) gene activation
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钙通道阻滞剂氨氯地平通过 p21(Waf1/Cip1) 基因激活发挥抗增殖作用
DOI：
10.1096/fj.04-1662com
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
L. Block
中科院分区：
文献类型：
--
作者：
R. Ziesche;V. Petkov;C. Lambers;P. Erne;L. Block
血管平滑肌细胞（VSMC）的增殖有助于动脉粥样硬化斑块的进展。钙通道阻滞剂已被证明可以减少VSMC增殖，但其潜在的分子机制尚不清楚。p21（Waf 1/Cip 1）是细胞周期进程的有效抑制剂。在这里，我们证明了在体外，p21（Waf 1/Cip 1）的从头合成被10−6至10−8 M的p21激活。我们发现，p21（Waf 1/Cip 1）的β-依赖性激活涉及糖皮质激素受体（GR）和C/EBP-α的作用。潜在途径显然涉及促分裂原活化蛋白激酶或蛋白激酶C的作用，但不涉及细胞外信号相关激酶或细胞内钙的变化。Ampase诱导的p21（Waf 1/Cip 1）启动子活性和锡永被C/EBP-α反义寡核苷酸或GR拮抗剂RU 486消除。氨氯地平依赖的细胞增殖抑制作用可被RU 486（10−8 M）（58% ±29%）、靶向C/EBP-α的反义寡核苷酸（91%±26%）或靶向p21（Waf 1/Cip 1）的反义mRNA（96%± 32%，n=6）部分逆转;乱序反义寡核苷酸或靶向C/EBP-β的反义寡核苷酸无效。这些数据表明，抗增殖作用是通过诱导p21（Waf 1/Cip 1）基因来实现的，这可以解释这种广泛使用的心血管治疗药物的有益隐性作用，而不仅仅是作为血管松弛剂的作用。Ziesche河，Petkov，V.，兰伯斯角，Erne，P.，布洛克，L-H。钙离子通道阻滞剂PGEX通过p21（Waf 1/Cip 1）基因激活发挥其抗增殖作用。FASEBJ。18，1516-1523（2004）
Proliferation of vascular smooth muscle cells (VSMC) contributes to the progression of athero¬sclerotic plaques. Calcium channel blockers have been shown to reduce VSMC proliferation, but the underlying molecular mechanism remains unclear. p21(Waf1/Cip1) is a potent inhibitor of cell cycle progression. Here, we demonstrate that amlodipine (10−6 to 10−8 M) activates de novo synthesis of p21(Waf1/Cip1) in vitro. We show that amlodipine‐dependent activation of p21(Waf1/Cip1) involves the action of the glucocorticoid receptor (GR) and C/EBP‐α. The underlying pathway apparently in¬volves the action of mitogen‐activated protein kinase or protein kinase C, but not of extracellular signal‐related kinase or changes of intracellular calcium. Amlodipine‐induced p21(Waf1/Cip1) promoter activity and expres¬sion were abrogated by C/EBP‐α antisense oligonucle¬otide or by the GR antagonist RU486. Amlodipinedependent inhibition of cell proliferation was partially reversed by RU486 at 10−8 M (58% ±29%), antisense oligonucleotides targeting C/EBP‐α (91%±26%), or antisense mRNAs targeting p21(Waf1/Cip1) (96%±32%, n=6);scrambled antisense oligonucleotides or those directed against C/EBP‐β were ineffective. The data suggest that the anti‐proliferative action of amlodipine is achieved by induction of the p21 (Waf1/Cip1) gene, which may explain beneficial covert effects of this widely used cardiovascular therapeutic drug beyond a more limited role as a vascular relaxant.—Ziesche, R., Petkov, V., Lambers, C., Erne, P., Block, L.‐H. The calcium channel blocker amlodipine exerts its antiproliferative action via p21(Waf1/Cip1) gene activation. FASEBJ. 18, 1516–1523 (2004)
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影响因子：
3.3
作者：
Park, JS;Qiao, L;Dent, P
通讯作者：
Dent, P
DOI：
10.1073/pnas.87.14.5378
发表时间：
1990-07
影响因子：
11.1
作者：
S. Maity;T. Vuorio;B. Crombrugghe
通讯作者：
S. Maity;T. Vuorio;B. Crombrugghe
影响因子：
0.8
作者：
A. Ruiz-Torres;R. Lozano;J. Melón;R. Carraro
通讯作者：
A. Ruiz-Torres;R. Lozano;J. Melón;R. Carraro
DOI：
10.1161/01.atv.0000023428.69244.49
发表时间：
2002-08-01
影响因子：
8.7
作者：
Nathe, TJ;Deou, J;Daum, G
通讯作者：
Daum, G
血管平滑肌细胞中修饰的低密度脂蛋白激活 MAPK。
DOI：
10.1152/jappl.2001.91.3.1412
发表时间：
2001
期刊：
Journal of applied physiology (Bethesda, Md. : 1985)
影响因子：
--
作者：
Velarde,V;Jenkins,AJ;Christopher,J;Lyons,TJ;Jaffa,AA
通讯作者：
Jaffa,AA