Abstract 15320: Increased Glycolysis Activity in Macrophages Contributes to the Progression of Abdominal Aortic Aneurysm
Purpose: Although mechanisms underlying the progression of abdominal aortic aneurysm (AAA) are complex, the increased metabolic activity with chronic inflammation in the aortic wall has been suggested. This study investigated the glucose metabolism in aneurysmal walls by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging in human subjects, and tested the hypothesis whether the increased metabolic activity might contribute to the pathogenesis of AAA development.
Methods and Results: Seventeen consecutive patients with atherosclerosis-associated AAA for elective open surgical repair (69±8 years old, male; 77%, AAA size; 50±13 mm, means±SD) underwent PET/computed tomography one day before surgery, and the AAA tissues were collected during surgical repair. Standardized uptake value (SUVmax) for 18F-FDG to the AAA walls was associated with protein expressions of glucose transporter (GLUT)-1 (r=0.706, p<0.0001) and GLUT-3 (r=0.415, p=0.013) at thirty-five corresponding sites in the AAA tissues, assessed by Western blot. The magnitude of GLUT-3 protein expression was significantly (r=0.415, p=0.013) correlated with zymographic MMP-9 activity, co-localized in macrophages. In monocytic cell line U937 induced by 10 nmol/l phorbol 12-myristate 13-acetate (n=4) or ex vivo culture obtained from human aneurysmal tissues (n=6), glucose transport inhibitions abrogated the MMP-9 activity in these cells/tissues. Furthermore, the inhibition of glycolysis activity with intra-peritoneal administration of 2-deoxyglucose (DG) for 28 days significantly (p<0.0001) attenuated the dilatation of abdominal aorta induced by peri-aortic application of CaCl2 (sham, 0.49±0.04 mm (n=10); CaCl2, 0.96±0.18 mm (n=14); CaCl2+2-DG, 0.62±0.08 mm (n=12)) in 8-week-old C57BL/6J male mice, accompanied by the decreases in MMP-9 activity and the accumulation of inflammatory cells in the adventitial layers.
Conclusions: This study suggests that increased glucose metabolic activity in macrophages contribute to the pathogenesis of AAA development by modulating matrix degrading enzyme, while the pharmacological intervention of glycolysis activity in this cell type might be the potential therapeutic target for the aneurysm progression.
- © 2010 by American Heart Association, Inc.