Abstract
HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors (statins) have been suggested to attenuate abdominal aortic aneurysm (AAA) growth. However, the effects of statins in human AAA tissues are not fully elucidated. The aim of this study was to investigate the direct effects of statins on proinflammatory molecules in human AAA walls in ex vivo culture. Simvastatin strongly inhibited the activation of nuclear factor (NF)-κB induced by tumor necrosis factor (TNF)-α in human AAA walls, but showed little effect on c-jun N-terminal kinase (JNK) activation. Simvastatin, as well as pitavastatin significantly reduced the secretion of matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-2 and epithelial neutrophil-activating peptide (CXCL5) under both basal and TNF-α-stimulated conditions. Similar to statins, the Rac1 inhibitor NSC23766 significantly inhibited the activation of NF-κB, accompanied by a decreased secretion of MMP-9, MCP-2 and CXCL5. Moreover, the effect of simvastatin and the JNK inhibitor SP600125 was additive in inhibiting the secretion of MMP-9, MCP-2 and CXCL5. These findings indicate that statins preferentially inhibit the Rac1/NF-κB pathway to suppress MMP-9 and chemokine secretion in human AAA, suggesting a mechanism for the potential effect of statins in attenuating AAA progression.
Highlights
Abdominal aortic aneurysm (AAA), which is a segmental dilatation of the abdominal aorta, is a common and life-threatening disease, especially in older men [1,2]
We used tumor necrosis factor (TNF)-α, because it is elevated in both serum and aneurysm walls of patients with abdominal aortic aneurysm (AAA) [33,34] and implicated in AAA pathogenesis [35]
CXCL5 secretion (82% reduction compared to control, p = 0.0109; Figure 6C). These data suggested that the Rac1/nuclear factor (NF)-κB and jun N-terminal kinase (JNK) pathways work in parallel to cause the secretion of matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-2 and CXCL5 in human AAA walls
Summary
Abdominal aortic aneurysm (AAA), which is a segmental dilatation of the abdominal aorta, is a common and life-threatening disease, especially in older men [1,2]. Nuclear factor (NF)-κB, play a key role in regulating the expression of proinflammatory mediators, including cytokines, and in activating MMPs in AAA and that inhibiting these signals is highly effective in treating experimental AAA [7,8,9]. Based on ex vivo culture analyses, statins reduce the secretion of proinflammatory proteins, including MMP-9 and monocyte chemoattractant protein (MCP)-1, in human AAA walls [17,18,19]. The aim of this study was to elucidate the direct effects of statins on proinflammatory molecules in human AAA tissues. Using an ex vivo culture system, we show that statins primarily inhibit the NF-κB pathway to suppress the secretion of chemokines and MMP-9 in human AAA walls
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