Abstract 5539: Tenascin-c Has a Protective Role During the Development of Abdominal Aortic Aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is an important healthcare problem for which non-surgical treatment is not available. Recently we reported that c-Jun N-terminal kinase-targeted pharmacotherapy can cause the regression of AAA by regulating inflammation and abnormal metabolism of extracellular matrix (ECM). To realize the pharmacotherapy, it is essential to develop the therapeutic biomarker that is involved in the pathogenesis and reflects the disease activity of AAA. We previously reported that tenascin-C (TN-C), an ECM protein, is an appropriate biomarker and can be used for the bioimaging of the inflammatory sites in several inflammatory diseases such as myocarditis. In this study, we tested if TN-C is a suitable biomarker for AAA. The tissue expression of TN-C was highest in human AAA with the diameter of 45–55 mm, the phase when AAA starts to progress rapidly. TN-C expression in individual aneurysms was highest at the transitional zone between normal and aneurysmal tissue where inflammatory process is most active. In mouse model of AAA induced by periaortic application of CaCl2, TN-C expression increased 4 to 6 weeks after the CaCl2 treatment that coincided with the rapid progression of AAA. Next, we examined if TN-C is involved in the pathogenesis of AAA by creating mouse model with periaortic application of CaCl2 followed by continuous infusion of angiotensin II in wild type (WT) and TN-C knockout (KO) mice. Surprisingly, 5 out of 15 TN-C KO mice developed large suprarenal aneurysms, while none of 14 WT mice did. Histologically, TN-C KO mice showed much more severe inflammation and destruction of elastic lamellae compared to WT. This may be because TN-C-deficient vascular smooth muscle cells express much higher cathepsin S, an elastolytic protease, and inflammatory mediators such as pentraxin 3. These results indicate that TN-C is expressed at the active lesion of AAA and critically involved in the pathogenesis by protecting aorta against tissue destruction. Because serum TN-C reflects the severity of inflammation and is also suitable for bioimaging in various inflammatory diseases, current study suggests that TN-C is an excellent candidate for the therapeutic biomarker and a potential therapeutic target for AAA.