Abstract 11285: JNK Isoforms Have Opposing Roles in Development of Acute Aortic Dissection
Acute aortic dissection is a common life-threatening disease. Although dysregulation of extracellular matrix has been suggested to cause aortic dissection, the underlying mechanisms remain largely unknown. Previously we reported that activation of c-Jun N-terminal kinase (JNK) shifts the balance of extracellular matrix metabolism toward degradation and leads to the development of abdominal aortic aneurysm. In this study, we investigated the roles of JNK, which has two isoforms, in the development of aortic dissection in mice. First, we created a model of aortic dissection by continuous infusion of angiotensin II in 20-week-old male mice. After seven days of angiotensin II infusion, wild-type mice and JNK2-deficient mice developed aortic dissection with an incidence of 32% (6 of 19) and 8% (1 of 13), respectively. Activation of JNK after three days of angiotensin II infusion was demonstrated in the aorta of wild-type mice but not in that of JNK2-deficient mice. Surprisingly, JNK1-deficient mice demonstrated activation of JNK in the aorta and a higher incidence of aortic dissection (71%, 5 of 7). The different effects of angiotensin II among these mice were independent of changes in blood pressure. Furthermore, we examined protein levels of enzymes related to extracellular matrix metabolism in cultured mouse aortic smooth muscle cells. Matrix metalloproteinase-2 was almost undetectable in the conditioned media of cells derived from JNK2-deficient mice, while it was readily detected in that of JNK1-deficient or wild-type cells. In addition, mRNA expression of lysyl oxidase was significantly increased in JNK2-deficient cells compared with wild-type cells, whereas it was significantly decreased in JNK1-deficient cells compared with wild-type cells. These results suggest that JNK1 and JNK2 have distinct and even opposing roles in the development of acute aortic dissection in mice.
- © 2013 by American Heart Association, Inc.