Abstract 13731: Activation of Focal Adhesion Kinase Leads to the Development and Progression of Abdominal Aortic Aneurysm in Mice
Introduction: Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammation, which contributes to the pathological remodeling of extracellular matrix. Focal adhesion kinase (FAK) is involved in the interactions between cells and extracellular matrix, and has been suggested to regulate the remodeling of extracellular matrix.
Hypothesis: We assessed the hypothesis that FAK plays a pivotal role in the development of AAA.
Methods and Results: Aortic wall specimens were obtained from patients that underwent aortic surgery (AAA; n=25, non-AAA; n=8). Levels of activated FAK were significantly increased in AAA walls compared with non-AAA walls (2.8 ± 2.3 fold, p<0.05). Activated FAK was localized to macrophages in the outer media and adventitia of AAA walls. We performed a comprehensive analysis of proteins secreted from mouse macrophages in vitro. The FAK inhibitor PF573228 significantly reduced the secretion of monocyte chemoattractant protein-1 and matrix metalloproteinase-9 in macrophages after stimulation with tumor necrosis factor-alpha. Further, we created AAA in C57BL/6 male mice by periaortic application of calcium chloride to investigate the role of FAK activation in vivo. From just after application of calcium chloride, mice were treated daily with PF573228 or vehicle for 6 weeks. Treatment of mice with PF573228 significantly prevented the increase in aortic diameter (PF573228; 0.84 ± 0.08 mm, vehicle; 1.19 ± 0.18 mm, p<0.01). Treatment with PF573228 also reduced inflammatory cell infiltration and disruption of the elastic lamellae. In an additional experiment, PF573228 or vehicle was administered daily from weeks 3 to 6 after application of calcium chloride. Interestingly, delayed treatment with PF573228 significantly inhibited the progression of aneurysmal dilatation (PF573228; 0.88 ± 0.18 mm, vehicle; 1.25 ± 0.27 mm, p<0.05).
Conclusions: Our results indicate a critical role for FAK activation in the development and progression of AAA in vivo, indicating that FAK represents a novel therapeutic target for preventing and treating AAA.
Author Disclosures: T. Harada: None. K. Yoshimura: None. O. Yamashita: None. K. Ueda: None. N. Morikage: None. K. Hamano: None.
- © 2015 by American Heart Association, Inc.