Abstract
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. To determine the role of KLF5 in AAA formation and macrophage infiltration into AAAs. 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. 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.
Highlights
Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease characterized by the remodeling of the aortic wall
Our data suggest that Krüppel-like factor 5 (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
KLF5 Is Upregulated in Human and Experimental AAA To investigate the roles of KLF5 in human aortic aneurysms, we initially determined KLF5 expression in AAA and normal aortic tissues
Summary
AAA tissue specimens were obtained in the operating room from 11 male patients undergoing elective open AAA repair. Nonaneurysmal infrarenal aortic wall tissue specimens were obtained from organ donors to serve as nonaneurysmal controls (n=7). Each of the surgical patients gave informed signed consent before donating tissue. All tissue specimens were taken after a protocol approved by the Human Tissue Research Committee of Hebei Medical University. One portion of each aortic wall specimen was fixed overnight in 10% neutral buffered formalin and processed for routine embedding in paraffin. An adjacent portion was snap-frozen in liquid nitrogen, stored at −80°C, and subsequently used for protein and nucleic acid extraction
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