Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.
PLoS One. 2013 Apr 30;8(4):e63424. doi: 10.1371/journal.pone.0063424. Print 2013.
Angiotensin II (Ang II) plays a major role in the pathogenesis of cardiac fibrosis in hypertension. It is known that Ang II induces TGF-β1 expression. How transcription mediates Ang II-induced TGF-β1 expression, as well as its contribution to cardiac fibrosis, is unknown. We studied the role of Krüppel-like family transcription factors in Ang II-induced myofibroblast formation. We found that among the Krüppel-like family members, Krüppel-like factor 4 (Klf4) was the highest expressed form in isolated cardiac fibroblasts after Ang II treatment. Klf4 increased expression of α-SMA and collagen, as well as increased myofibroblast formation. ChIP assays showed that Klf4 specifically bound to the TGF-β1 promoter. Deletion and mutagenesis analysis showed that the sites at -184∼-180 bp and -45∼-41 bp in the TGF-β1 promoter were responsible for Klf4 transactivation of the TGF-β1 promoter. Our studies demonstrate that Klf4 plays a pivotal role in Ang II-induced cardiac myofibroblast differentiation and collagen synthesis through transcriptional upregulation of TGF-β1.
血管紧张素 II（Ang II）在高血压中心脏纤维化的发病机制中起主要作用。已知 Ang II 诱导 TGF-β1 的表达。转录如何介导 Ang II 诱导的 TGF-β1 表达及其对心脏纤维化的贡献尚不清楚。我们研究了 Krüppel 样家族转录因子在 Ang II 诱导的肌成纤维细胞形成中的作用。我们发现，在 Krüppel 样家族成员中，Krüppel 样因子 4（Klf4）是 Ang II 处理后分离的心肌成纤维细胞中表达最高的形式。Klf4 增加了 α-SMA 和胶原的表达，并增加了肌成纤维细胞的形成。ChIP 分析表明，Klf4 特异性结合到 TGF-β1 启动子上。缺失和突变分析表明，TGF-β1 启动子上-184∼-180 bp 和-45∼-41 bp 处的位点负责 Klf4 对 TGF-β1 启动子的转录激活。我们的研究表明，Klf4 通过 TGF-β1 的转录上调在 Ang II 诱导的心脏成纤维细胞分化和胶原合成中起关键作用。
