Abstract 427: c-Jun N-terminal Kinase 2 Translates Mechanical Stress to Inflammatory Signal in Macrophages and Promotes Progression of Abdominal Aortic Aneurysm In Vivo
Recently we reported that activation of c-Jun N-terminal kinase (JNK) accelerates chronic inflammation and degradation of extracellular matrix during development of abdominal aortic aneurysm (AAA). We also demonstrated that pharmacological inhibition of JNK causes tissue healing and regression of established AAA in mice. However, the causes for JNK activation and the following chronic inflammation in AAA have not been elucidated. We hypothesized that mechanical stress induces and sustains the inflammation through JNK activation during the progression of AAA. To test this hypothesis, we cultured mouse abdominal macrophages or aortic smooth muscle cells on a silicone membrane and applied uniaxial 10% cyclic strains at 30 Hz. After pretreatment with lipopolysaccharide to induce pro-interleukin-1 beta (pro-IL-1 beta) protein expression, the mechanical strain caused the increase in phosphorylation of JNK2 and the rapid cleavage and the release of IL-1 beta in macrophages but not in aortic smooth muscle cells, suggesting that macrophage is the primary sensor of mechanical stress. IL-1 beta is a major pro-inflammatory cytokine that is proposed to participate in the pathogenesis of AAA. Interestingly, the release of IL-1 beta induced by the mechanical strain was abolished in JNK2-deficient macrophages, indicating the critical role of JNK2 in the linkage between mechanical stress and proinflammatory signaling. To evaluate this role of JNK2 during the development of AAA in vivo, we applied 0.5 M calcium chloride to the infrarenal aortae of wild type, JNK1-deficient or JNK2-deficient mice. Six weeks after application of calcium chloride, wild type and JNK1-deficient mice showed the significant increase in aortic diameter (54±32% and 51±30%, respectively), along with marked inflammatory infiltration and destruction of elastic lamellae. In contrast, JNK2-deficient mice were distinctly protected from the development of AAA (10±25%). In conclusion, mechanical stress activates JNK2 in macrophages that is essential for the release of IL-1 beta and the progression of AAA in animal model.