Wang Baiqiu, Haldar Saptarsi M, Lu Yuan, Ibrahim Osama A, Fisch Sudeshna, Gray Susan, Leask Andrew, Jain Mukesh K
Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine/University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
J Mol Cell Cardiol. 2008 Aug;45(2):193-7. doi: 10.1016/j.yjmcc.2008.05.005. Epub 2008 May 20.
Cardiac fibrosis is a hallmark feature of pathologic remodeling of the heart in response to hemodynamic or neurohormonal stress. Accumulating evidence implicates connective tissue growth factor (CTGF) as a key mediator of this process. Our group has previously identified Kruppel-Like Factor 15 (KLF15) as an important regulator of cardiac remodeling in response to stress; however, the role of this transcription factor in cardiac fibrosis has not been reported. Here we provide evidence that treatment of neonatal rat ventricular fibroblasts (NRVFs) with the potent pro-fibrotic agent Transforming Growth Factor-beta1 (TGFbeta1) strongly reduces KLF15 expression while inducing the pro-fibrotic factor CTGF. Adenoviral overexpression of KLF15 inhibits basal and TGFbeta1-induced CTGF expression in NRVFs. Furthermore, hearts from KLF15-/- mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. From a mechanistic standpoint, KLF15 inhibits basal and TGFbeta1-mediated induction of the CTGF promoter. Chromatin Immunoprecipitation (ChIP) and electrophoretic mobility shift assays demonstrate that KLF15 inhibits recruitment of the co-activator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. Consistent with this observation, KLF15 mediated repression of the CTGF promoter is rescued by P/CAF overexpression. Our result implicates KLF15 as a novel negative regulator of CTGF expression and cardiac fibrosis.
心脏纤维化是心脏在血流动力学或神经激素应激反应下病理性重塑的一个标志性特征。越来越多的证据表明，结缔组织生长因子（CTGF）是这一过程的关键介质。我们的研究小组之前已确定 Kruppel 样因子 15（KLF15）是应激反应中心脏重塑的重要调节因子；然而，该转录因子在心脏纤维化中的作用尚未见报道。在此，我们提供证据表明，用强效促纤维化因子转化生长因子-β1（TGFβ1）处理新生大鼠心室成纤维细胞（NRVF）会强烈降低 KLF15 的表达，同时诱导促纤维化因子 CTGF 的表达。KLF15 的腺病毒过表达抑制了 NRVF 中基础和 TGFβ1 诱导的 CTGF 表达。此外，接受主动脉缩窄的 KLF15 - / - 小鼠心脏中 CTGF 水平升高且出现纤维化。从机制角度来看，KLF15 抑制基础和 TGFβ1 介导的 CTGF 启动子诱导。染色质免疫沉淀（ChIP）和电泳迁移率变动分析表明，KLF15 抑制共激活因子 P/CAF 募集到 CTGF 启动子，而对 Smad3 与 DNA 的结合无显著影响。与这一观察结果一致，P/CAF 的过表达挽救了 KLF15 介导的 CTGF 启动子抑制。我们的结果表明 KLF15 是 CTGF 表达和心脏纤维化的一种新型负调节因子。
