Dong Ma1, Bin Zheng1, Toru Suzuki1, Ruonan Zhang1, Chunyang Jiang1, Disi Bai1, Weina Yin1, Zhan Yang1, Xinhua Zhang1, Lianguo Hou1, Hong Zhan1, Jin-Kun Wen2. 1. 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.). 2. 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.
Abstract
RATIONALE: 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. METHODS AND 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.
RATIONALE: 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. METHODS AND 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: Steven J Forrester; George W Booz; Curt D Sigmund; Thomas M Coffman; Tatsuo Kawai; Victor Rizzo; Rosario Scalia; Satoru Eguchi Journal: Physiol Rev Date: 2018-07-01 Impact factor: 37.312
Authors: Aniket Mishra; Rainer Malik; Tsuyoshi Hachiya; Tuuli Jürgenson; Shinichi Namba; Daniel C Posner; Frederick K Kamanu; Masaru Koido; Quentin Le Grand; Mingyang Shi; Yunye He; Marios K Georgakis; Ilana Caro; Kristi Krebs; Yi-Ching Liaw; Felix C Vaura; Kuang Lin; Bendik Slagsvold Winsvold; Vinodh Srinivasasainagendra; Livia Parodi; Hee-Joon Bae; Ganesh Chauhan; Michael R Chong; Liisa Tomppo; Rufus Akinyemi; Gennady V Roshchupkin; Naomi Habib; Yon Ho Jee; Jesper Qvist Thomassen; Vida Abedi; Jara Cárcel-Márquez; Marianne Nygaard; Hampton L Leonard; Chaojie Yang; Ekaterina Yonova-Doing; Maria J Knol; Adam J Lewis; Renae L Judy; Tetsuro Ago; Philippe Amouyel; Nicole D Armstrong; Mark K Bakker; Traci M Bartz; David A Bennett; Joshua C Bis; Constance Bordes; Sigrid Børte; Anael Cain; Paul M Ridker; Kelly Cho; Zhengming Chen; Carlos Cruchaga; John W Cole; Phil L de Jager; Rafael de Cid; Matthias Endres; Leslie E Ferreira; Mirjam I Geerlings; Natalie C Gasca; Vilmundur Gudnason; Jun Hata; Jing He; Alicia K Heath; Yuk-Lam Ho; Aki S Havulinna; Jemma C Hopewell; Hyacinth I Hyacinth; Michael Inouye; Mina A Jacob; Christina E Jeon; Christina Jern; Masahiro Kamouchi; Keith L Keene; Takanari Kitazono; Steven J Kittner; Takahiro Konuma; Amit Kumar; Paul Lacaze; Lenore J Launer; Keon-Joo Lee; Kaido Lepik; Jiang Li; Liming Li; Ani Manichaikul; Hugh S Markus; Nicholas A Marston; Thomas Meitinger; Braxton D Mitchell; Felipe A Montellano; Takayuki Morisaki; Thomas H Mosley; Mike A Nalls; Børge G Nordestgaard; Martin J O'Donnell; Yukinori Okada; N Charlotte Onland-Moret; Bruce Ovbiagele; Annette Peters; Bruce M Psaty; Stephen S Rich; Jonathan Rosand; Marc S Sabatine; Ralph L Sacco; Danish Saleheen; Else Charlotte Sandset; Veikko Salomaa; Muralidharan Sargurupremraj; Makoto Sasaki; Claudia L Satizabal; Carsten O Schmidt; Atsushi Shimizu; Nicholas L Smith; Kelly L Sloane; Yoichi Sutoh; Yan V Sun; Kozo Tanno; Steffen Tiedt; Turgut Tatlisumak; Nuria P Torres-Aguila; Hemant K Tiwari; David-Alexandre Trégouët; Stella Trompet; Anil Man Tuladhar; Anne Tybjærg-Hansen; Marion van Vugt; Riina Vibo; Shefali S Verma; Kerri L Wiggins; Patrik Wennberg; Daniel Woo; Peter W F Wilson; Huichun Xu; Qiong Yang; Kyungheon Yoon; Iona Y Millwood; Christian Gieger; Toshiharu Ninomiya; Hans J Grabe; J Wouter Jukema; Ina L Rissanen; Daniel Strbian; Young Jin Kim; Pei-Hsin Chen; Ernst Mayerhofer; Joanna M M Howson; Marguerite R Irvin; Hieab Adams; Sylvia Wassertheil-Smoller; Kaare Christensen; Mohammad A Ikram; Tatjana Rundek; Bradford B Worrall; G Mark Lathrop; Moeen Riaz; Eleanor M Simonsick; Janika Kõrv; Paulo H C França; Ramin Zand; Kameshwar Prasad; Ruth Frikke-Schmidt; Frank-Erik de Leeuw; Thomas Liman; Karl Georg Haeusler; Ynte M Ruigrok; Peter Ulrich Heuschmann; W T Longstreth; Keum Ji Jung; Lisa Bastarache; Guillaume Paré; Scott M Damrauer; Daniel I Chasman; Jerome I Rotter; Christopher D Anderson; John-Anker Zwart; Teemu J Niiranen; Myriam Fornage; Yung-Po Liaw; Sudha Seshadri; Israel Fernández-Cadenas; Robin G Walters; Christian T Ruff; Mayowa O Owolabi; Jennifer E Huffman; Lili Milani; Yoichiro Kamatani; Martin Dichgans; Stephanie Debette Journal: Nature Date: 2022-09-30 Impact factor: 69.504