Inhibition of Development of Abdominal Aortic Aneurysm by Glycolysis Restriction
Inhibition of Development of Abdominal Aortic Aneurysm by Glycolysis Restriction
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DOI：
10.1161/atvbaha.111.237065
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发表时间：
2012-06-01
影响因子：
8.7
通讯作者：
Kitamura, Kazuo
中科院分区：
文献类型：
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作者：
Tsuruda, Toshihiro;Hatakeyama, Kinta;Kitamura, Kazuo
目的：腹主动脉瘤发生的机制尚不清楚。我们假设葡萄糖转运蛋白上调导致的葡萄糖代谢加速与腹主动脉瘤的发生有关。方法和结果：用正电子发射断层扫描技术增强修饰的葡萄糖类似物18氟脱氧葡萄糖在人腹主动脉瘤中的积聚，并用Western印迹法评估葡萄糖转运蛋白-1和-3的蛋白表达。葡萄糖转运蛋白-3的表达强度与酶谱基质金属蛋白酶-9的活性相关。C57BL/6J雄性小鼠腹主动脉注射CaCl2引起的腹主动脉扩张或血管紧张素Ⅱ基因敲除雄性小鼠的动脉瘤形成明显减少。在佛波酯-12-肉豆蔻酸酯-13-醋酸酯诱导的单核细胞系或人动脉瘤组织的体外培养中，2-脱氧葡萄糖抑制了这些细胞/组织的基质金属蛋白酶-9活性和白介素6的表达。此外，2-脱氧葡萄糖还可抑制单核细胞的存活/增殖及其与血管内皮细胞的黏附。结论：本研究提示主动脉壁糖酵解活性增强参与了动脉瘤的发生发展。此外，对糖酵解活性的药物干预可能是治疗这种疾病的潜在靶点。(动脉血栓血管生物)2012；32：1410-1417。)
Objective-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.Methods and Results-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 CaCl2 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.Conclusion-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. (Arterioscler Thromb Vasc Biol. 2012;32:1410-1417.)