Kruppel-like factor 4 is required for the expression of vascular smooth muscle cell differentiation marker genes induced by all-trans retinoic acid.
Kruppel-like factor 4 is required for the expression of vascular smooth muscle cell differentiation marker genes induced by all-trans retinoic acid.
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DOI：
10.1093/jb/mvn068
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发表时间：
2008-09
影响因子：
2.7
通讯作者：
Chao Wang;Mei Han;Xin-ming Zhao;J. Wen
中科院分区：
文献类型：
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作者：
Chao Wang;Mei Han;Xin-ming Zhao;J. Wen
KRüppel样因子4(KLF4)参与了血管平滑肌细胞(VSMCs)的表型转化。全反式维甲酸(ATRA)抑制VSMC增殖，诱导VSMC分化。然而，KLF4在全反式维甲酸诱导的VSMC表型调节中的作用尚不清楚。在这里，我们发现全反式维甲酸处理后，VSMCs的增殖和迁移受到显著抑制，KLF4和VSMC分化标志基因SM22pha和SMα-肌动蛋白(α-SMA)表达上调。同时，KLF4靶基因P53表达上调，VSMC去分化标志基因非肌球蛋白重链B(SMemb)表达下调。我们还发现，KLF4在VSMC中的过表达增加了P53、SM22α和α-SMA的表达，但降低了SMemb和VSMC的增殖和迁移。KLF4特异性小干扰RNA(SiRNA)阻断KLF4的表达可阻断ATRA对P53、SM22α和α-SMA表达的诱导作用，并中和ATRA对SMemb表达和VSMC增殖和迁移的抑制作用。因此，我们的研究结果提示，KLF4是全反式维甲酸诱导VSMC分化标志基因表达所必需的，该转录因子是VSMC维甲酸作用的关键介质之一。
Krüppel-like factor 4 (KLF4) is involved in phenotypic modulation of vascular smooth muscle cells (VSMCs). All-trans retinoic acid (ATRA) inhibits VSMC proliferation and induces VSMC differentiation. However, the role of KLF4 in ATRA-elicited VSMC phenotypic modulation remains unclear. Here, we show that treatment of VSMCs with ATRA resulted in significant inhibition of proliferation and migration of VSMCs, as well as up-regulation of KLF4 and the VSMC differentiation marker genes SM22alpha and SM alpha-actin (alpha-SMA). At the same time, the KLF4 target gene p53 was up-regulated, while the VSMC dedifferentiation marker gene nonmuscle myosin heavy chain-B (SMemb) was down-regulated. We also show that overexpression of KLF4 in VSMCs increased the expression of p53, SM22alpha and alpha-SMA, but decreased the expression of SMemb and VSMC proliferation and migration. Silencing of KLF4 expression by KLF4-specific small interfering RNA (siRNA) abrogated the inducing effects of ATRA on p53, SM22alpha and alpha-SMA expression and neutralized the inhibitory effects of ATRA on SMemb expression and VSMC proliferation and migration. Thus, our data suggest that KLF4 is required for the expression of VSMC differentiation marker genes induced by ATRA and that this transcription factor is one of the key mediators of retinoid actions in VSMCs.