Nagai Ryozo, Shindo Takayuki, Manabe Ichiro, Suzuki Toru, Kurabayashi Masahiko
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
Adv Exp Med Biol. 2003;538:57-65; discussion 66. doi: 10.1007/978-1-4419-9029-7_5.
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.
心脏生物学和血管生物学需要相互关联地进行研究，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、血管生成以及细胞外基质的产生。我们之前报道过KLF5/BTEB2，一种类Krüppel锌指型转录因子，它能激活多种在表型调节的平滑肌细胞中被激活的基因启动子，比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）、诱导型一氧化氮合酶（iNOS）、血小板衍生生长因子 -A（PDGF-A）、早期生长反应蛋白 -1（Egr-1）以及血管内皮生长因子（VEGF）受体，至少在体外是这样。随着血管发育，KLF5/BTEB2的mRNA水平会下调，但在因血管损伤而产生的新生内膜中会上调。有丝分裂原刺激通过MEK1和Egr-1激活KLF5/BTEB2基因表达。染色质免疫沉淀分析表明，在血管紧张素II刺激下，KLF5/BTEB2会被诱导并结合PDGF-A基因的启动子。为了确定KLF5/BTEB2在心血管重塑中的作用，我们在小鼠中靶向KLF5/BTEB2基因。纯合子小鼠导致早期胚胎致死，而异合子小鼠看起来正常。然而，在受到外部应激时，杂合子的动脉表现出平滑肌和外膜细胞激活水平降低。此外，持续输注血管紧张素II会诱导心脏纤维化和肥大。我们还发现视黄酸受体α（RARα）与KLF5/BTEB2结合，并且一种强效合成RAR激动剂Am80能抑制血管紧张素II诱导的心脏肥大。这些结果表明，KLF5/BTEB2是一种重要的转录因子，它不仅会导致平滑肌表型调节，还会引起心脏肥大和纤维化。
