FABP4 induces vascular smooth muscle cell proliferation and migration through a MAPK-dependent pathway.
FABP4 induces vascular smooth muscle cell proliferation and migration through a MAPK-dependent pathway.
复制标题
FABP4 通过 MAPK 依赖性途径诱导血管平滑肌细胞增殖和迁移。
DOI：
10.1371/journal.pone.0081914
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Vallvé JC
中科院分区：
文献类型：
--
作者：
Girona J;Rosales R;Plana N;Saavedra P;Masana L;Vallvé JC
血管平滑肌细胞的迁移和增殖在动脉粥样硬化病变的发展中起着至关重要的作用。本研究检测了脂肪酸结合蛋白4（FABP 4）对人冠状动脉平滑肌细胞（HCASMCs）迁移和增殖的影响，FABP 4是一种与心血管风险、内皮功能障碍和促炎作用相关的脂肪因子。 DNA 5-溴-2 ′-脱氧尿苷（BrdU）掺入实验表明，FABP 4显著诱导HCASMCs的增殖，并呈剂量依赖性，在120 ng/ml时达到最大刺激效应（13% vs. unstimulated cells，p<0.05）。抗FABP 4抗体（40 ng/ml）显著抑制诱导的细胞增殖，证明了FABP 4增殖作用的特异性。FABP 4以剂量依赖性方式显著诱导HCASMC迁移，初始效应为60 ng/ml（12% vs.未刺激的细胞，p<0.05）。时程研究表明，与未刺激的细胞相比，从4小时（23%对17%，p<0.05）至12小时（74%对59%，p <0.05），FABP 4显著增加细胞迁移。LY-294002（5 μM）和PD 98059（10 μM）预处理阻断FABP 4诱导的HCASMC增殖和迁移，表明激酶途径的激活。在分子水平上，我们观察到MAPK通路的上调而不激活Akt。我们发现，FABP 4诱导核转录因子c-jun和c-myc的活性形式，这是由MAPK级联调节，并增加下游基因cyclin D1和MMP 2，CCL 2，和fibulin 4和5的表达，参与细胞周期调控和细胞迁移。 这些发现表明FABP 4对HCASMC的迁移和增殖的直接影响，表明这种脂肪因子在血管重塑中的作用。总之，这些结果表明，FABP 4诱导的DNA合成和细胞迁移主要是通过MAPK依赖性途径介导的，该途径激活HCASMC中的转录因子c-jun和c-myc。
The migration and proliferation of vascular smooth muscle cells play crucial roles in the development of atherosclerotic lesions. This study examined the effects of fatty acid binding protein 4 (FABP4), an adipokine that is associated with cardiovascular risk, endothelial dysfunction and proinflammatory effects, on the migration and proliferation of human coronary artery smooth muscle cells (HCASMCs). A DNA 5-bromo-2′-deoxy-uridine (BrdU) incorporation assay indicated that FABP4 significantly induced the dose-dependent proliferation of HCASMCs with a maximum stimulatory effect at 120 ng/ml (13% vs. unstimulated cells, p<0.05). An anti-FABP4 antibody (40 ng/ml) significantly inhibited the induced cell proliferation, demonstrating the specificity of the FABP4 proliferative effect. FABP4 significantly induced HCASMC migration in a dose-dependent manner with an initial effect at 60 ng/ml (12% vs. unstimulated cells, p<0.05). Time-course studies demonstrated that FABP4 significantly increased cell migration compared with unstimulated cells from 4 h (23%vs. 17%, p<0.05) to 12 h (74%vs. 59%, p<0.05). Pretreatment with LY-294002 (5 µM) and PD98059 (10 µM) blocked the FABP4-induced proliferation and migration of HCASMCs, suggesting the activation of a kinase pathway. On a molecular level, we observed an up-regulation of the MAPK pathway without activation of Akt. We found that FABP4 induced the active forms of the nuclear transcription factors c-jun and c-myc, which are regulated by MAPK cascades, and increased the expression of the downstream genes cyclin D1 and MMP2, CCL2, and fibulin 4 and 5, which are involved in cell cycle regulation and cell migration. These findings indicate a direct effect of FABP4 on the migration and proliferation of HCASMCs, suggesting a role for this adipokine in vascular remodelling. Taken together, these results demonstrate that the FABP4-induced DNA synthesis and cell migration are mediated primarily through a MAPK-dependent pathway that activates the transcription factors c-jun and c-myc in HCASMCs.
登录
查看更多内容
影响因子：
9.8
作者：
Elmasri, Harun;Ghelfi, Elisa;Yu, Chen-wei;Traphagen, Samantha;Cernadas, Manuela;Cao, Haiming;Shi, Guo-Ping;Plutzky, Jorge;Sahin, Mustafa;Hotamisligil, Gokhan;Cataltepe, Sule
通讯作者：
Cataltepe, Sule
影响因子：
5.3
作者：
Lee K;Santibanez-Koref M;Polvikoski T;Birchall D;Mendelow AD;Keavney B
通讯作者：
Keavney B
影响因子：
39.3
作者：
Peeters, Wouter;de Kleijn, Dominique P. V.;Pasterkamp, Gerard
通讯作者：
Pasterkamp, Gerard
影响因子：
7.3
作者：
Lee, Mary Y. K.;Li, Huiying;Vanhoutte, Paul M.
通讯作者：
Vanhoutte, Paul M.
DOI：
10.1111/j.1365-2362.2011.02553.x
发表时间：
2012-01-01
影响因子：
5.5
作者：
Aragones, Gemma;Ferre, Raimon;Masana, Lluis
通讯作者：
Masana, Lluis