title: Inhibition of KLF5-Myo9b-RhoA Pathway-Mediated Podosome Formation in Macrophages Ameliorates Abdominal Aortic Aneurysm.
abstract: BACKGROUND
  Abdominal aortic aneurysms (AAAs) are characterized by pathological remodeling of the aortic wall. Although both increased Krüppel-like factor 5 (KLF5) expression and macrophage infiltration have been implicated in vascular remodeling, the role of KLF5 in macrophage infiltration and AAA formation remains unclear.
  
  
  OBJECTIVE
  To determine the role of KLF5 in AAA formation and macrophage infiltration into AAAs.
  
  
  RESULTS
  KLF5 expression was significantly increased in human AAA tissues and in 2 mouse models of experimental AAA. Moreover, in myeloid-specific Klf5 knockout mice (myeKlf5-/-mice), macrophage infiltration, medial smooth muscle cell loss, elastin degradation, and AAA formation were markedly decreased. In cell migration and time-lapse imaging analyses, the migration of murine myeKlf5-/-macrophages was impaired, and in luciferase reporter assays, KLF5 activated Myo9b (myosin IXB) transcription by direct binding to the Myo9b promoter. In subsequent coimmunostaining studies, Myo9b was colocalized with filamentous actin, cortactin, vinculin, and Tks5 in the podosomes of phorbol 12,13-dibutyrate-treated macrophages, indicating that Myo9b participates in podosome formation. Gain- and loss-of-function experiments showed that KLF5 promoted podosome formation in macrophages by upregulating Myo9b expression. Furthermore, RhoA-GTP levels increased after KLF5 knockdown in macrophages, suggesting that KLF5 lies upstream of RhoA signaling. Finally, Myo9b expression was increased in human AAA tissues, located in macrophages, and positively correlated with AAA size.
  
  
  CONCLUSIONS
  These data are the first to indicate that KLF5-dependent regulation of Myo9b/RhoA is required for podosome formation and macrophage migration during AAA formation, warranting consideration of the KLF5-Myo9b-RhoA pathway as a therapeutic target for AAA treatment.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, China (D.M., B.Z., R.Z., C.J., D.B., W.Y., Z.Y., X.Z., L.H., J.-k.W.); School of Public Health, North China University of Science and Technology, China (D.M., D.B.); Department of Cardiovascular Sciences, University of Leicester, UK (T.S.); Department of Thoracic Surgery, Tianjin Union Medicine Centre, China (C.J.); Department of Cardiovascular Medicine, Jichi Medical University, Tochigi and Graduate School of Medicine, The University of Tokyo, Japan (H.Z.).
authors.forename: Dong
authors.initials: D
authors.lastname: Ma
authors.affiliation: From the Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, China (D.M., B.Z., R.Z., C.J., D.B., W.Y., Z.Y., X.Z., L.H., J.-k.W.); School of Public Health, North China University of Science and Technology, China (D.M., D.B.); Department of Cardiovascular Sciences, University of Leicester, UK (T.S.); Department of Thoracic Surgery, Tianjin Union Medicine Centre, China (C.J.); Department of Cardiovascular Medicine, Jichi Medical University, Tochigi and Graduate School of Medicine, The University of Tokyo, Japan (H.Z.).
authors.forename: Bin
authors.initials: B
authors.lastname: Zheng
authors.affiliation: From the Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, China (D.M., B.Z., R.Z., C.J., D.B., W.Y., Z.Y., X.Z., L.H., J.-k.W.); School of Public Health, North China University of Science and Technology, China (D.M., D.B.); Department of Cardiovascular Sciences, University of Leicester, UK (T.S.); Department of Thoracic Surgery, Tianjin Union Medicine Centre, China (C.J.); Department of Cardiovascular Medicine, Jichi Medical University, Tochigi and Graduate School of Medicine, The University of Tokyo, Japan (H.Z.).
authors.forename: Toru
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: From the Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, China (D.M., B.Z., R.Z., C.J., D.B., W.Y., Z.Y., X.Z., L.H., J.-k.W.); School of Public Health, North China University of Science and Technology, China (D.M., D.B.); Department of Cardiovascular Sciences, University of Leicester, UK (T.S.); Department of Thoracic Surgery, Tianjin Union Medicine Centre, China (C.J.); Department of Cardiovascular Medicine, Jichi Medical University, Tochigi and Graduate School of Medicine, The University of Tokyo, Japan (H.Z.).
authors.forename: Ruonan
authors.initials: R
authors.lastname: Zhang
authors.affiliation: From the Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, China (D.M., B.Z., R.Z., C.J., D.B., W.Y., Z.Y., X.Z., L.H., J.-k.W.); School of Public Health, North China University of Science and Technology, China (D.M., D.B.); Department of Cardiovascular Sciences, University of Leicester, UK (T.S.); Department of Thoracic Surgery, Tianjin Union Medicine Centre, China (C.J.); Department of Cardiovascular Medicine, Jichi Medical University, Tochigi and Graduate School of Medicine, The University of Tokyo, Japan (H.Z.).
authors.forename: Chunyang
authors.initials: C
authors.lastname: Jiang
authors.affiliation: From the Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, China (D.M., B.Z., R.Z., C.J., D.B., W.Y., Z.Y., X.Z., L.H., J.-k.W.); School of Public Health, North China University of Science and Technology, China (D.M., D.B.); Department of Cardiovascular Sciences, University of Leicester, UK (T.S.); Department of Thoracic Surgery, Tianjin Union Medicine Centre, China (C.J.); Department of Cardiovascular Medicine, Jichi Medical University, Tochigi and Graduate School of Medicine, The University of Tokyo, Japan (H.Z.).
authors.forename: Disi
authors.initials: D
authors.lastname: Bai
authors.affiliation: From the Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, China (D.M., B.Z., R.Z., C.J., D.B., W.Y., Z.Y., X.Z., L.H., J.-k.W.); School of Public Health, North China University of Science and Technology, China (D.M., D.B.); Department of Cardiovascular Sciences, University of Leicester, UK (T.S.); Department of Thoracic Surgery, Tianjin Union Medicine Centre, China (C.J.); Department of Cardiovascular Medicine, Jichi Medical University, Tochigi and Graduate School of Medicine, The University of Tokyo, Japan (H.Z.).
authors.forename: Weina
authors.initials: W
authors.lastname: Yin
authors.affiliation: From the Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, China (D.M., B.Z., R.Z., C.J., D.B., W.Y., Z.Y., X.Z., L.H., J.-k.W.); School of Public Health, North China University of Science and Technology, China (D.M., D.B.); Department of Cardiovascular Sciences, University of Leicester, UK (T.S.); Department of Thoracic Surgery, Tianjin Union Medicine Centre, China (C.J.); Department of Cardiovascular Medicine, Jichi Medical University, Tochigi and Graduate School of Medicine, The University of Tokyo, Japan (H.Z.).
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yang
authors.affiliation: From the Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, China (D.M., B.Z., R.Z., C.J., D.B., W.Y., Z.Y., X.Z., L.H., J.-k.W.); School of Public Health, North China University of Science and Technology, China (D.M., D.B.); Department of Cardiovascular Sciences, University of Leicester, UK (T.S.); Department of Thoracic Surgery, Tianjin Union Medicine Centre, China (C.J.); Department of Cardiovascular Medicine, Jichi Medical University, Tochigi and Graduate School of Medicine, The University of Tokyo, Japan (H.Z.).
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, China (D.M., B.Z., R.Z., C.J., D.B., W.Y., Z.Y., X.Z., L.H., J.-k.W.); School of Public Health, North China University of Science and Technology, China (D.M., D.B.); Department of Cardiovascular Sciences, University of Leicester, UK (T.S.); Department of Thoracic Surgery, Tianjin Union Medicine Centre, China (C.J.); Department of Cardiovascular Medicine, Jichi Medical University, Tochigi and Graduate School of Medicine, The University of Tokyo, Japan (H.Z.).
authors.forename: Lianguo
authors.initials: L
authors.lastname: Hou
authors.affiliation: From the Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, China (D.M., B.Z., R.Z., C.J., D.B., W.Y., Z.Y., X.Z., L.H., J.-k.W.); School of Public Health, North China University of Science and Technology, China (D.M., D.B.); Department of Cardiovascular Sciences, University of Leicester, UK (T.S.); Department of Thoracic Surgery, Tianjin Union Medicine Centre, China (C.J.); Department of Cardiovascular Medicine, Jichi Medical University, Tochigi and Graduate School of Medicine, The University of Tokyo, Japan (H.Z.).
authors.forename: Hong
authors.initials: H
authors.lastname: Zhan
authors.affiliation: From the Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, China (D.M., B.Z., R.Z., C.J., D.B., W.Y., Z.Y., X.Z., L.H., J.-k.W.); School of Public Health, North China University of Science and Technology, China (D.M., D.B.); Department of Cardiovascular Sciences, University of Leicester, UK (T.S.); Department of Thoracic Surgery, Tianjin Union Medicine Centre, China (C.J.); Department of Cardiovascular Medicine, Jichi Medical University, Tochigi and Graduate School of Medicine, The University of Tokyo, Japan (H.Z.). wjk@hebmu.edu.cn.
authors.forename: Jin-Kun
authors.initials: JK
authors.lastname: Wen
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism* / Q000517:prevention & control*; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis* / Q000172:deficiency; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009218:Myosins / Q000096:biosynthesis* / Q000172:deficiency; D000069261:Podosomes / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis* / Q000172:deficiency
chemical_list: C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; C113469:myosin IXB; D009218:Myosins; D020742:rhoA GTP-Binding Protein
keywords: KLF5; Myo9b; RhoA; aneurysm; macrophage; motility; myosin; podosome