Abstract 13646: Temporal Systemic Deletion of Tumor Necrosis Factor-α Converting Enzyme Inhibits Development of Abdominal Aortic Aneurysm
Background: Aortic expression of tumor necrosis factor (TNF)-α and subsequent inflammation contribute to the development of abdominal aortic aneurysm (AAA). However, the role of TNF-α converting enzyme (Tace), also known as ADAM17, in the development of AAA remains unclear.
Methods and Results: We obtained human aortic wall samples (n=10) during surgical repair of AAA. Autopsy samples from normal aorta were served as control (n=6). Immunoblotting showed that expression of TNF-α and Tace was upregulated in AAA compared with control samples. To evaluate the role of Tace, we generate temporal systemic deletion of Tace by the inducible Mx-1 Cre transgene. AAA was induced in Mx-1 Cre transgenic mice (Cre) and wild-type littermates (CON) by periaortic application of CaCl2 (AAA/Cre, AAA/CON, n=8 each group). NaCl (0.9%) was substituted for CaCl2 in sham-operated mice (Sham/Cre, Sham/CON, n=8 each group). All mice were treated with intraperitoneal injection of polyinosinic-polycytidylic acid for activating Cre and sacrificed 6 weeks after the operation. Aortic diameter was larger in AAA/CON than in Sham/CON and Sham/Cre. Ablation of Tace resulted in a decreased aortic diameter compared with AAA/CON (1.3 ± 0.1 vs. 0.9 ± 0.1 mm, p< 0.01). Elastica von Gieson staining showed that wavy morphology of the elastic lamellae was flattened in AAA/CON compared with Sham/CON and Sham/Cre, but was preserved in AAA/Cre. Increased activity of matrix metalloproteinase (MMP)-9 in AAA/CON was reduced in AAA/Cre (−35% vs. AAA/CON, p<0.01). Immunohistochemistry showed less Mac-3+ monocytes/macrophages in periaortic tissues in AAA/Cre compared with AAA/CON (0.7±0.8 vs. 5.2±2.5/HPF, p<0.05). Increased aortic wall mRNA expression of CD68, monocyte chemotactic protein-1, TNF-α and intercellular adhesion molecule-1and increased protein expression of p-JNK, TNF-α and Tace in AAA were attenuated by Tace ablation (all p< 0.05).
Conclusions: Tace was overexpressed in the aortic wall of human and experimental AAA. Post-natal ablation of Tace prevented AAA development, in association with reduction of MMP-9 activity, inflammatory cells infiltration, JNK activity, and preservation of ECM structure. These findings suggest a crucial role of Tace in the development of AAA.
- © 2010 by American Heart Association, Inc.