Abstract 15481: Focal Adhision Kinase Promotes the Fatal Destruction of Aortic Wall in Aortic Dissection in Mice

• Published in: Circulation (New York, N.Y.) N.Y.), 2018-11, Vol.138 (Suppl_1 Suppl 1), p.A15481-A15481
• Main Authors: Majima, Ryohei, Aoki, Hiroki, Hashimoto, Yohei, Ito, Sohei, Hayashi, Makiko, Ohno-Urabe, Satoko, Furusho, Aya, Nishida, Norifumi, Hirakata, Saki, Fukumoto, Yoshihiro
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539

Aortic dissection (AD) is a fatal disease in which the aortic media suddenly fails. AD involving the ascending aorta (Stanford type A) is particularly at the high risk of fatal outcome, for which surgical replacement of the damaged aorta with an artifical graft is highly recommended. Currently, no pharmacological therapy is available to limit the destruction of the aortic walls in AD, because its molecular pathogenesis is unknown. Recently, we discovered that MRTF-A, a mechanosensitive transcriptional regulator that is under the control of actin dynamics, is critically involved in AD pathogenesis. This discovery prompted us to investigate the role of focal adhesion kinase (FAK), which transduces the mechanostress to the actin dynamics, in AD pathogenesis. We used a mouse model of AD that was created by continuous infusion of beta-aminopropionitrile, a collagen crosslink inhibitor, and angiotensin II (BAPN+AngII), which caused AD in all mice with approximately 60% of mortality due to the AD rupture within 2 weeks. Western blot analysis for activated (phosphorylated) FAK (pFAK) showed that BAPN+AngII administration resulted in the activation of FAK in the aortic tissue before AD development. Immunohistochemical staining for pFAK also revealed that FAK was strongly activated in the aortic walls after BAPN+AngII infusion. Double immunofluorescence staining for pFAK and smooth muscle alpha-actin showed that FAK was activated both in smooth muscle cells and in non-smooth muscle cells after the BAPN + AngII challenge. Significantly, administration of PND-1186, an orally available FAK inhibitor, resulted in the significant reduction in the severity of AD especially in the aortic arch including the ascending aorta. Furthermore, the mortality was improved from 63.6% to 33.3% by PND-1186 administration. These findings demonstrated that FAK plays a central role in AD pathogenesis, possibly by transducing the pathological stress to the tissue destructive response in the aortic walls. We propose that FAK is a potential therapeutic target to limit the fatal destruction of aortic walls in AD.