Abstract 12907: Involvement of IL-6 in Pathogenesis of Abdominal Aortic Aneurysm
Abdominal aortic aneurysm (AAA) is the most common aortic disease in adult that is characterized by chronic inflammation and destruction of aortic walls. Although AAA is the leading cause of death, no pharmacotherapy has been established. It has been reported that human AAA is associated with the increase in a number of proinflammatory cytokines. However, it is unclear which cytokine plays a central role in pathogenesis of AAA. In this study, we first examined the secretions of a panel of 50 proinflammatory cytokines in ex vivo cultures of human AAA tissues obtained from three individuals during the surgical repair of AAA. We found that IL-6 was one of the most highly secreted cytokines among the 50 proinflammatory cytokines. Gene expression analysis of human AAA tissues revealed that JAK/STAT-dependent cytokines were most abundantly expressed in the transitional zone from the normal aorta to the aneurysm, where the inflammation and tissue destruction were most active, suggesting the importance of JAK/STAT pathway in AAA pathogenesis. Second, we created the mouse model of AAA by periaortic application of CaCl2, which showed IL-6 expression, STAT3 activation, cellular infiltration, and destruction of elastic lamellae at the lesion of AAA. The formation of AAA was also associated with the increase in nuclear staining of NFkB and expression of MMP-9 in aortic tissue. Systemic administration of the IL-6 receptor blocking antibody in mice suppressed the STAT3 activation, nuclear localization of NFkB and expression of MMP-9 in the aortic tissue, indicating the decrease in the inflammatory and tissue destructive response. Consequently, the IL-6 receptor blocking antibody effectively preserved the tissue architecture of the aortic walls and prevented the formation of AAA. These findings indicate that IL-6 pathway is critically involved in the inflammation of AAA, suggesting that the IL-6 pathway is a promising target for the pharmacotherapy of AAA.
- © 2013 by American Heart Association, Inc.