二氢吡啶类钙拮抗剂对血管平滑肌细胞早期生长反应基因表达及细胞生长的作用

Action of dihydropyridine calcium antagonists on early growth response gene expression and cell growth in vascular smooth muscle cells.

作者信息

Ko Y, Totzke G, Graack G H, Heidgen F J, Meyer zu Brickwedde M K, Düsing R, Vetter H, Sachinidis A

机构信息

Medizinische Universitäts-Poliklinik, Bonn, Germany.

出版信息

J Hypertens. 1993 Nov;11(11):1171-8.

PMID:8301097

Abstract

OBJECTIVE

Evidence suggests that calcium antagonists may suppress vascular smooth muscle cell (VSMC) growth and proliferation, which may be a crucial step in the pathogenesis of hypertension and atherosclerosis.

DESIGN

The effects of the dihydropyridine calcium antagonists nifedipine, nitrendipine, nisoldipine, nimodipine and isradipine on cell growth induced by platelet-derived growth factor (PDGF)-AB and angiotensin II (Ang II), and expression of the transcription factors c-fos and early-growth response gene 1 (egr-1) were investigated.

METHODS

Proliferation of VSMC in culture was measured by [3H]-thymidine incorporation into cell DNA and by cell count. Expression of c-fos and egr-1 messenger RNA (mRNA) was determined by the Northern blot technique.

RESULTS

All of the calcium antagonists blunted the PDGF-induced rise in VSMC DNA synthesis. The inhibitory potency of isradipine on PDGF-stimulated DNA synthesis was approximately 10-fold that of the other calcium antagonists used, isradipine having a half-maximal inhibitory concentration (IC50) of (4.2 +/- 0.16) x 10(-7) mol/l. The calcium antagonists investigated also inhibited Ang II-induced DNA synthesis. Isradipine (10(-6) mol/l) completely abolished the PDGF-induced cell proliferation. Both PDGF (50 ng/ml) and Ang II (10(-7) mol/l) induced c-fos and egr-1 mRNA expression, having maximum effect after 30 min. In the case of c-fos, pre-incubation with 5 x 10(-6) mol/l isradipine led to a decrease in both Ang II- and PDGF-induced expression of this immediate-early gene. The expression of egr-1 was not affected by pre-incubation with 5 x 10(-6) mol/l isradipine.

CONCLUSIONS

All calcium antagonists investigated in the present study inhibited cell growth. Isradipine was more potent in blocking growth factor-induced cell growth than the other calcium antagonists studied. The inhibitory effect of the dihydropyridine calcium antagonists appears to be dependent on the expression of c-fos.

摘要

目的

有证据表明钙拮抗剂可能抑制血管平滑肌细胞（VSMC）的生长和增殖，这可能是高血压和动脉粥样硬化发病机制中的关键步骤。

设计

研究了二氢吡啶类钙拮抗剂硝苯地平、尼群地平、尼索地平、尼莫地平和伊拉地平对血小板衍生生长因子（PDGF）-AB和血管紧张素II（Ang II）诱导的细胞生长以及转录因子c-fos和早期生长反应基因1（egr-1）表达的影响。

方法

通过[3H]胸腺嘧啶掺入细胞DNA和细胞计数来测量培养的VSMC的增殖。用Northern印迹技术测定c-fos和egr-1信使核糖核酸（mRNA）的表达。

结果

所有钙拮抗剂均抑制了PDGF诱导的VSMC DNA合成增加。伊拉地平对PDGF刺激的DNA合成的抑制效力约为所用其他钙拮抗剂的10倍，伊拉地平的半数最大抑制浓度（IC50）为（4.2±0.16）×10-7mol/L。所研究的钙拮抗剂也抑制了Ang II诱导的DNA合成。伊拉地平（10-6mol/L）完全消除了PDGF诱导的细胞增殖。PDGF（50ng/ml）和Ang II（10-7mol/L）均诱导c-fos和egr-1 mRNA表达，30分钟后达到最大效应。对于c-fos，用5×10-6mol/L伊拉地平预孵育导致Ang II和PDGF诱导的该即刻早期基因表达均下降。用5×10-6mol/L伊拉地平预孵育对egr-1的表达没有影响。