Kim Ha Won, Blomkalns Andra L, Ogbi Mourad, Thomas Manesh, Gavrila Daniel, Neltner Bonnie S, Cassis Lisa A, Thompson Robert W, Weiss Robert M, Lindower Paul D, Blanco Victor M, McCormick Michael L, Daugherty Alan, Fu Xiaoming, Hazen Stanley L, Stansfield Brian K, Huo Yuqing, Fulton David J, Chatterjee Tapan, Weintraub Neal L
Division of Cardiology, Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia.
Department of Emergency Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia.
Am J Physiol Heart Circ Physiol. 2017 Dec 1;313(6):H1168-H1179. doi: 10.1152/ajpheart.00296.2017. Epub 2017 Sep 29.
Oxidative stress plays a fundamental role in abdominal aortic aneurysm (AAA) formation. Activated polymorphonuclear leukocytes (or neutrophils) are associated with AAA and express myeloperoxidase (MPO), which promotes inflammation, matrix degradation, and other pathological features of AAA, including enhanced oxidative stress through generation of reactive oxygen species. Both plasma and aortic MPO levels are elevated in patients with AAA, but the role of MPO in AAA pathogenesis has, heretofore, never been investigated. Here, we show that MPO gene deletion attenuates AAA formation in two animal models: ANG II infusion in apolipoprotein E-deficient mice and elastase perfusion in C57BL/6 mice. Oral administration of taurine [1% or 4% (wt/vol) in drinking water], an amino acid known to react rapidly with MPO-generated oxidants like hypochlorous acid, also prevented AAA formation in the ANG II and elastase models as well as the CaCl application model of AAA formation while reducing aortic peroxidase activity and aortic protein-bound dityrosine levels, an oxidative cross link formed by MPO. Both MPO gene deletion and taurine supplementation blunted aortic macrophage accumulation, elastin fragmentation, and matrix metalloproteinase activation, key features of AAA pathogenesis. Moreover, MPO gene deletion and taurine administration significantly attenuated the induction of serum amyloid A, which promotes ANG II-induced AAAs. These data implicate MPO in AAA pathogenesis and suggest that studies exploring whether taurine can serve as a potential therapeutic for the prevention or treatment of AAA in patients merit consideration. Neutrophils are abundant in abdominal aortic aneurysm (AAA), and myeloperoxidase (MPO), prominently expressed in neutrophils, is associated with AAA in humans. This study demonstrates that MPO gene deletion or supplementation with the natural product taurine, which can scavenge MPO-generated oxidants, can prevent AAA formation, suggesting an attractive potential therapeutic strategy for AAA.
氧化应激在腹主动脉瘤（AAA）形成中起关键作用。活化的多形核白细胞（即中性粒细胞）与AAA相关，并表达髓过氧化物酶（MPO），MPO可促进炎症、基质降解以及AAA的其他病理特征，包括通过产生活性氧增强氧化应激。AAA患者的血浆和主动脉MPO水平均升高，但迄今为止，MPO在AAA发病机制中的作用从未被研究过。在此，我们表明MPO基因缺失可减轻两种动物模型中的AAA形成：载脂蛋白E缺陷小鼠中的血管紧张素II输注和C57BL/6小鼠中的弹性蛋白酶灌注。口服牛磺酸[饮用水中1%或4%（重量/体积）]，一种已知能与MPO产生的氧化剂如次氯酸快速反应的氨基酸，也能预防ANG II和弹性蛋白酶模型以及AAA形成的氯化钙应用模型中的AAA形成，同时降低主动脉过氧化物酶活性和主动脉蛋白结合二酪氨酸水平，后者是由MPO形成的氧化交联产物。MPO基因缺失和补充牛磺酸均能抑制主动脉巨噬细胞积聚、弹性蛋白片段化和基质金属蛋白酶激活，这些是AAA发病机制的关键特征。此外，MPO基因缺失和给予牛磺酸显著减弱了血清淀粉样蛋白A的诱导，血清淀粉样蛋白A可促进ANG II诱导的AAA。这些数据表明MPO参与AAA发病机制，并提示探索牛磺酸是否可作为预防或治疗患者AAA的潜在疗法的研究值得考虑。中性粒细胞在腹主动脉瘤（AAA）中大量存在，而在中性粒细胞中显著表达的髓过氧化物酶（MPO）与人类AAA相关。本研究表明，MPO基因缺失或补充可清除MPO产生的氧化剂的天然产物牛磺酸可预防AAA形成，提示了一种有吸引力的AAA潜在治疗策略。
