Inhibition of KLF5-Myo9b-RhoA Pathway-Mediated Podosome Formation in Macrophages Ameliorates Abdominal Aortic Aneurysm
Dong Ma
Bin Zheng
Toru Suzuki
Ruonan Zhang
Chunyang Jiang
Disi Bai
Weina Yin
Zhan Yang
Xinhua Zhang
Lianguo Hou
Hong Zhan
Jin-kun Wen
2381/43144
https://figshare.le.ac.uk/articles/journal_contribution/Inhibition_of_KLF5-Myo9b-RhoA_Pathway-Mediated_Podosome_Formation_in_Macrophages_Ameliorates_Abdominal_Aortic_Aneurysm/10237994
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.
2019-01-17 15:08:59
KLF5
Myo9b
RhoA
aneurysm
macrophage
motility
myosin
podosome
Animals
Aortic Aneurysm, Abdominal
Cell Line
HEK293 Cells
Humans
Kruppel-Like Transcription Factors
Macrophages
Male
Mice
Mice, Knockout
Myosins
Podosomes
Signal Transduction
rhoA GTP-Binding Protein