Abstract 603: Combinatorial Effect of Statins and JNK Inhibitor on Proinflammatory Signaling in Human Abdominal Aortic Aneurysm Tissue
Recent studies suggested that statins attenuate the growth of human abdominal aortic aneurysm (AAA), which is a common and life-threatening disease. We and others reported that c-Jun N-terminal kinase (JNK) and nuclear factor (NF)-kappaB mediate the inflammatory response in AAA pathogenesis. Thus, we hypothesized that statins may suppress JNK and/or NF-kappaB activities to reduce the inflammatory mediators. To test the hypothesis, we first examined the effect of statins on cytokine secretion using ex vivo culture of human AAA walls. By the comprehensive analysis of 79 cytokines and chemokines in the conditioned media of AAA culture, we found that simvastatin (10 microM) and pitavastatin (20 microM) significantly reduced secretions of monocyte chemotactic protein (MCP)-1, -2 and -3, and CXCL-5. The effect of statins was completely reversed by addition of mevalonate. Tumor necrosis factor (TNF)-alpha, which has been implicated in AAA pathogenesis, activated both JNK and NF-kappaB and induced secretions of the MCPs, CXCL-5 and matrix metalloproteinase (MMP)-9. Simvastatin strongly suppressed nuclear translocation of NF-kappaB, but minimally attenuated JNK phosphorylation after stimulation by TNF-alpha. NSC23766, a Rac1 inhibitor, also prevented the nuclear translocation of NF-kappaB and reduced secretion of CXCL5 and MMP-9, consistent with the previous reports that statins suppress Rac1 activity. Interestingly, the inhibitory effect of simvastatin and SP600125, a JNK inhibitor, on MMP-9 secretion was additive at various doses, suggesting that NF-kappaB and JNK pathways work in parallel to cause MMP-9 secretion. These findings demonstrate that statins preferentially inhibit NF-kappaB signaling with less effect on JNK activity to suppress the secretion of chemokines and MMP-9 in human AAA tissue, providing a possible mechanism for the inhibitory effect of statins on the progression of AAA. Combination of JNK inhibitor and statin may provide a novel and more effective therapeutic opportunity for AAA.