Abstract 600: c-Jun N-terminal Kinase 2 is Required for Development of Abdominal Aortic Aneurysm in Mice
Aortic aneurysm has been regarded as a progressive and irreversible disease. Recently we reported that c-Jun N-terminal kinase (JNK) causes the abnormal metabolism of extracellular matrix (ECM) in the pathogenesis of abdominal aortic aneurysm (AAA) by enhancing tissue degradation and suppressing tissue repair. We also demonstrated that pharmacological inhibition of JNK causes regression of established AAA in mice. Aortic tissue expresses JNK1 and JNK2 isoforms, and isoform-specific JNK inhibition may provide an optimized therapy. Although it was reported by others that expression of JNK2, but not JNK1, is upregulated in human aortic aneurysms, it is not known whether each isoform has a specific role in the pathogenesis of AAA. Thus, the aim of this study was to investigate the roles of JNK1 and JNK2 during the progression of AAA. For induction of AAA, we applied 0.5 M CaCl2 to the infrarenal aortae of mice deficient for JNK1 or JNK2. The wild type littermates were used as a control. Six weeks after application of CaCl2, wild type and JNK1−/− mice showed the significant increase in aortic diameter (54+/−32% and 51+/−30%, respectively). In contrast, JNK2−/− mice were distinctly protected from AAA development (10+/−25%). Matrix metalloproteinase-2 that causes ECM degradation during AAA development was almost undetectable in the conditioned media of vascular smooth muscle cells derived from JNK2−/− mice, while it was readily detected in that of JNK1−/− or wild-type cells. In addition, both lysyl oxidase that is a critical enzyme for ECM biosynthesis and transforming growth factor-beta that activates ECM biosynthesis were significantly increased in the conditioned media of JNK2−/− vascular smooth muscle cells, compared with JNK1−/− or wild-type cells. These findings demonstrate the critical role of JNK2 in the destructive ECM metabolism and the progression of AAA in a mouse model, suggesting a clinical implication of JNK2-specific inhibition for the treatment of AAA.