Complement Regulator CD59 Protects Against Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice

Background-Complement system, an innate immunity, has been well documented to play a critical role in many inflammatory diseases. However, the role of complement in the pathogenesis of abdominal aortic aneurysm, which is considered an immune and inflammatory disease, remains obscure. Methods and Results-Here, we evaluated the pathogenic roles of complement membrane attack complex and CD59, a key regulator that inhibits the membrane attack complex, in the development of abdominal aortic aneurysm. We demonstrated that in the angiotensin II-induced abdominal aortic aneurysm model, deficiency of the membrane attack complex regulator CD59 in ApoE-null mice (mCd59ab(-/-)/ApoE(-/-)) accelerated the disease development, whereas transgenic overexpression of human CD59 (hCD59ICAM-2(-/-)/ApoE(-/-)) in this model attenuated the progression of abdominal aortic aneurysm. The severity of aneurysm among these 3 groups positively correlates with C9 deposition, and/or the activities of MMP2 and MMP9, and/or the levels of phosphorylated c-Jun, c-Fos, IKK-alpha/beta, and p65. Furthermore, we demonstrated that the membrane attack complex directly induced gene expression of matrix metalloproteinase-2 and -9 in vitro, which required activation of the activator protein-1 and nuclear factor-kappa B signaling pathways. Conclusion-Together, these results defined the protective role of CD59 and shed light on the important pathogenic role of the membrane attack complex in abdominal aortic aneurysm. (Circulation. 2010; 121: 1338-1346.)