Abstract 5069: Loss of MHC Class II Transactivator Causes Abdominal Aortic Aneurysm
Th1 and/or Th2 cytokines produced by inflammatory cells may influence the outcome of arterial inflammation. Indeed, Th2 type cytokines predominate in human abdominal aortic aneurysm (AAA) lesions, while cells in stenotic atherosclerotic lesions preferentially express Th1 cytokines. The major histocompatibility complex (MHC) class II transactivator (C2ta) is a transcriptional co-activator responsible for IFNγ-inducible MHC class II expression on antigen-presenting cells. C2ta can also modulate IL-4 and MMPs. This study tested the hypothesis that C2ta deficiency could induce MMP expression and cause aortic aneurysm formation in atherogenic animals. Results: Real-time quantitative PCR and Western blot demonstrated that human AAA tissues express significantly less C2ta mRNA and lower HLA-DR protein levels than the atherosclerotic aortic tissue. In addition, human AAA tissues express significantly elevated MMP9 and MMP12 protein levels. 12-week-old male ApoE−/− and ApoE/C2ta−/− mice consumed a 1.25% cholesterol diet up to 8M. The abdominal aortic diameter below the renal artery branches of ApoE/C2ta−/− mice increased at 8M compared to the ApoE−/− mice (1.68±0.28 vs. 0.90±0.10 mm, mean± SD, p < 0.0001). The morphological analysis of the ApoE/C2ta−/− mice fed with 8M atherogenic diet showed fragmentation of the medial elastic lamellae and expanded luminal area, characterizing aortic aneurysm. ApoE/C2ta−/− mice had higher plasma levels of IL-4 and IL-10 (4.9±3.0 and 114.2±75.5 ng/mL, mean±SD, n=10) than ApoE−/− mice (1.9±2.2, p=0.0057; and 29.9±24.1 ng/mL, p=0.0062, respectively) after 8M on an atherogenic diet. Western blot and zymography showed significantly higher expression and activity of MMP9 and MMP12 in the aortic lesions of the ApoE/c2ta−/− compared to those of the ApoE−/− mice at 6M high-cholesterol diet. The aortic diameter of the triple deficient animals of ApoE/C2ta/MMP9 −/− and ApoE/C2ta/MMP12 −/− did not increase even after 8M on an atherogenic diet (0.76±0.21 mm, mean± SD, n=10; 0.68±0.10 mm, n=10, p <0.0001 vs. ApoE/C2ta−/−). Conclusion: This study illustrates a novel mechanism for Th2 dominant cytokine milieu in a subset of patients with aortic atherosclerosis and how impaired signaling of C2ta and IFN-γ promote AAA formation.
This research has received full or partial funding support from the American Heart Association, National Center.