Department of Internal Medicine, Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara Kiyotake, Miyazaki 889-1692, Japan.
Arterioscler Thromb Vasc Biol. 2012 Jun;32(6):1410-7. doi: 10.1161/ATVBAHA.111.237065. Epub 2012 Apr 12.
The mechanisms underlying abdominal aortic aneurysm development remain unknown. We hypothesized that acceleration of glucose metabolism with the upregulation of glucose transporters is associated with abdominal aortic aneurysm development.
Enhanced accumulation of the modified glucose analogue 18 fluoro-deoxyglucose by positron emission tomography imaging in the human abdominal aortic aneurysm was associated with protein expressions of glucose transporters-1 and -3, assessed by Western blot. The magnitude of glucose transporter-3 expression was correlated with zymographic matrix metalloproteinase-9 activity. Intraperitoneal administration of glycolysis inhibitor with 2-deoxyglucose significantly attenuated the dilatation of abdominal aorta induced by periaortic application of CaCl(2) in C57BL/6J male mice or reduced the aneurysmal formation in angiotensin II-infused apolipoprotein E knockout male mice. In monocytic cell line induced by phorbol 12-myristate 13-acetate or ex vivo culture obtained from human aneurysmal tissues, 2-deoxyglucose abrogated the matrix metalloproteinase-9 activity and interleukin-6 expression in these cells/tissues. Moreover, 2-deoxyglucose attenuated the survival/proliferation of monocytes and the adherence of them to vascular endothelial cells.
This study suggests that the enhanced glycolytic activity in aortic wall contributes to the pathogenesis of aneurysm development. In addition, pharmacological intervention in glycolytic activity might be a potential therapeutic target for the disorder.
腹主动脉瘤发展的机制尚不清楚。我们假设，葡萄糖转运蛋白的上调加速葡萄糖代谢与腹主动脉瘤的发展有关。
正电子发射断层扫描成像显示，人腹主动脉瘤中改良葡萄糖类似物 18 氟-脱氧葡萄糖的积累增加，通过 Western blot 检测到葡萄糖转运蛋白-1 和 -3 的蛋白表达增加。葡萄糖转运蛋白-3 的表达量与明胶酶谱基质金属蛋白酶-9 活性相关。腹腔内给予 2-脱氧葡萄糖抑制糖酵解，可显著减轻腹主动脉周围应用氯化钙诱导的 C57BL/6J 雄性小鼠腹主动脉扩张，或减少血管紧张素 II 输注的载脂蛋白 E 敲除雄性小鼠的动脉瘤形成。在佛波醇 12-肉豆蔻酸 13-乙酸诱导的单核细胞系或从人动脉瘤组织获得的体外培养物中，2-脱氧葡萄糖可阻断这些细胞/组织中的基质金属蛋白酶-9 活性和白细胞介素-6 表达。此外，2-脱氧葡萄糖可减弱单核细胞的存活/增殖以及它们与血管内皮细胞的黏附。
本研究提示主动脉壁中增强的糖酵解活性有助于动脉瘤发展的发病机制。此外，糖酵解活性的药理学干预可能是该疾病的潜在治疗靶点。
