Abstract 1164: Mast Cells Contribute to Pathogenesis in the Progression of Abdominal Aortic Aneuyrsm
Abdominal aortic aneurysm (AAA) is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation, while the mechanisms for progression of aneurysm are poorly understood. In the present study, we carried out histological study of AAA tissues of patients (75±1 years, Mean±SEM), and interventional animal and cell culture experiments to investigate the role of mast cells in the pathogenesis of AAA. The number of mast cells determined by positive staining for tryptase, a major neutral protease of human mast cell secretory granules, was found to increase in the outer media or adventitia of human AAA, compared to those in the control aorta (2.1±1.1/mm2 (n=57) vs. 0.6±0.4/mm2 (n=22), p<0.01), showing a positive correlation (r=0.442, p<0.01) between the cell number and the AAA diameter. Western blot demonstrated that the protein expressions of tryptase, stem cell factor (a ligand for c-kit) and the phosphorylation of c-kit were significantly (p<0.01) increased in the AAA tissues, compared with the control aorta. In the animal experiments, diameter of abdominal aorta of the control (+/+) rats was increased up to 55% at 14 days following peri-aortic application of 0.4 mol/L calcium chloride, but only a 13% increase in the mast cell-deficient mutant Ws/Ws rats. The AAA formation was accompanied by accumulation of mast cells, T-lymphocytes, interferon-γ positive cells and by activated matrix metalloproteinases (MMP)-2 and -9, reduced elastin levels and augmented angiogenesis in the aortic tissue, but these changes were much less in the Ws/Ws rats than in the control (+/+) rats. The pharmacological intervention with the mast cell stabilizer tranilast (400 mg/kg/day) for 14 days significantly (p<0.01) attenuated the AAA development in the control (+/+) rats. Co-culturing the mast cell line HMC-1 with the monocyte/macrophage cell line U937 significantly (p<0.01) augmented MMP-9 activity. Furthermore, 100 and 300 μmol/L of tranilast significantly (p<0.01) decreased MMP-9 activity in those cells. Collectively, these data suggest that mast cells may play important roles in the progression of AAA.