KLF5/BTEB2, a Krüppel-like zinc-finger type transcription factor, mediates both smooth muscle cell activation and cardiac hypertrophy.
KLF5/BTEB2, a Krüppel-like zinc-finger type transcription factor, mediates both smooth muscle cell activation and cardiac hypertrophy.
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DOI：
10.1007/978-1-4419-9029-7_5
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发表时间：
2003
影响因子：
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通讯作者：
R. Nagai;T. Shindo;I. Manabe;Toru Suzuki;M. Kurabayashi
中科院分区：
文献类型：
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作者：
R. Nagai;T. Shindo;I. Manabe;Toru Suzuki;M. Kurabayashi
心脏和血管生物学需要相互作用，因为它们具有许多共同的生物学特征，如局部肾素-血管紧张素系统的激活、血管生成和细胞外基质的产生。我们之前报道过KLF5/BTEB2，一种kr<s:1>样锌指型转录因子，至少在体外可以激活在表型调节的平滑肌细胞中激活的各种基因启动子，如非肌肉型肌球蛋白重链基因SMemb、纤溶酶原激活物抑制剂-1 （PAI-1）、iNOS、PDGF-A、Egr-1和VEGF受体。KLF5/BTEB2 mRNA水平在血管发育过程中下调，但在血管损伤产生的新生内膜中上调。有丝分裂刺激通过MEK1和Egr-1激活KLF5/BTEB2基因表达。染色质免疫沉淀实验显示，在血管紧张素II刺激下，KLF5/BTEB2被诱导并结合PDGF-A基因启动子。为了明确KLF5/BTEB2在心血管重塑中的作用，我们以小鼠KLF5/BTEB2基因为目标。纯合子小鼠导致早期胚胎死亡，而杂合子小鼠则明显正常。然而，在外部应激的作用下，杂合子的动脉平滑肌和外体细胞活化水平降低。此外，持续输注血管紧张素II可引起心肌纤维化和肥厚。我们还发现RARa与KLF5/BTEB2结合，而Am80（一种强效的合成RAR激动剂）可抑制血管紧张素ii诱导的心脏肥厚。这些结果表明，KLF5/BTEB2是一个重要的转录因子，不仅引起平滑肌表型调节，而且引起心肌肥大和纤维化。
Cardiac and vascular biology need to be approached interactively because they share many common biological features as seen in activation of the local renin-angiotensin system, angiogenesis, and extracellular matrix production. We previously reported KLF5/BTEB2, a Krüppel-like zinc-finger type transcription factor, to activate various gene promoters that are activated in phenotypically modulated smooth muscle cells, such as a nonmuscle type myosin heavy chain gene SMemb, plasminogen activator inhibitor-1 (PAI-1), iNOS, PDGF-A, Egr-1 and VEGF receptors at least in vitro. KLF5/BTEB2 mRNA levels are downregulated with vascular development but upregulated in neointima that is produced in response to vascular injury. Mitogenic stimulation activates KLF5/BTEB2 gene expression through MEK1 and Egr-1. Chromatin immunoprecipitation assay showed KLF5/BTEB2 to be induced and to bind the promoter of the PDGF-A gene in response to angiotensin II stimulation. In order to define the role of KLF5/BTEB2 in cardiovascular remodeling, we targeted the KLF5/BTEB2 gene in mice. Homozygous mice resulted in early embryonic lethality whereas heterozygous mice were apparently normal. However, in response to external stress, arteries of heterozygotes exhibited diminished levels of smooth muscle and adventitial cell activation. Furthermore, cardiac fibrosis and hypertrophy induced by continuous angiotensin II infusion. We also found that RARa binds KLF5/BTEB2, and that Am80, a potent synthetic RAR agonist, inhibits angiotensin II-induced cardiac hypertrophy. These results indicate that KLF5/BTEB2 is an essential transcription factor that causes not only smooth muscle phenotypic modulation but also cardiac hypertrophy and fibrosis.