Experimental and Clinical Vascular Biology Lab, Vascular and Endovascular Surgery Unit, San Martino Hospital and Department of Internal Medicine, Research Center of Cardiovascular Biology, University of Genoa, Genoa, Italy.
J Surg Res. 2011 Dec;171(2):e237-46. doi: 10.1016/j.jss.2011.07.041. Epub 2011 Aug 24.
BACKGROUND: Monocyte activation, macrophage infiltration, vascular oxidative stress and matrix proteolysis are inflammatory key steps contributing to abdominal aortic aneurysm (AAA) development. A phenotypical and functional heterogeneity is recognizable in monocytes by the differential expression of surface molecules: CD62L- subset corresponds to activated monocytes, while CD143/ACE surface expression increases during their differentiation into macrophages. In this work, Resveratrol, which is an antioxidant polyphenol with vasoprotective properties, has been evaluated for its potential to limit aneurysm development and monocyte-dependent inflammatory response in a model of elastase-induced AAA. METHODS: Male Sprague-Dawley rats received Resveratrol (10 mg/kg/die) (Rsv group, n=15) or vehicle (ethanol) alone (Et-OH group, n=15) continuously from 7 d before until 14 d after the AAA induction with elastase; five littermates were used as untreated control group (Ctr group, n=5). At the end of treatment, CD143 and CD62L monocyte expression was analyzed by flow cytometry, serum antioxidant capacity was evaluated using the TRAP method and circulating TNFα, and MMP-9 were measured with ELISA and gel zymography, respectively. Aortas were subjected to histology and immunohistochemistry for morphological analysis, macrophage infiltration, and MMP-9, TNFα, and VEGF expression. RESULTS: Resveratrol counteracted the CD62L-monocyte subset expansion, CD143 monocyte expression, and circulating levels of MMP-9 activity and TNFα associated to AAA induction. Similarly, treatment with Resveratrol significantly attenuated AAA expansion, vessel wall macrophage infiltration and MMP-9, VEGF, and TNFα expression, compared with AAA from Et-OH group. CONCLUSIONS: Resveratrol limited the monocyte-dependent inflammatory response, macrophage differentiation and aortic lumen enlargement in elastase-induced AAA. These data suggest that Resveratrol might be tested in selected patients with small AAA to modulate the early systemic and local inflammatory response associated to AAA progression.
背景：单核细胞激活、巨噬细胞浸润、血管氧化应激和基质蛋白水解是导致腹主动脉瘤（AAA）发展的炎症关键步骤。通过表面分子的差异表达，可以识别单核细胞的表型和功能异质性：CD62L-亚群对应于激活的单核细胞，而 CD143/ACE 表面表达在其分化为巨噬细胞的过程中增加。在这项工作中，白藜芦醇是一种具有血管保护作用的抗氧化多酚，它被评估了其在弹性蛋白酶诱导的 AAA 模型中限制动脉瘤发展和单核细胞依赖性炎症反应的潜力。
方法：雄性 Sprague-Dawley 大鼠在弹性蛋白酶诱导 AAA 前 7 天至 14 天连续给予白藜芦醇（10mg/kg/die）（Rsv 组，n=15）或单独给予乙醇（Et-OH 组，n=15）；5 只同窝仔鼠作为未处理对照组（Ctr 组，n=5）。在治疗结束时，通过流式细胞术分析 CD143 和 CD62L 单核细胞表达，使用 TRAP 法评估血清抗氧化能力，通过 ELISA 和凝胶酶谱法分别测量循环 TNFα 和 MMP-9。对主动脉进行组织学和免疫组织化学分析，以进行形态学分析、巨噬细胞浸润以及 MMP-9、TNFα 和 VEGF 表达。
结果：白藜芦醇抑制了与 AAA 诱导相关的 CD62L-单核细胞亚群扩张、CD143 单核细胞表达以及循环 MMP-9 活性和 TNFα 水平。与 Et-OH 组的 AAA 相比，白藜芦醇治疗还显著减轻了 AAA 扩张、血管壁巨噬细胞浸润以及 MMP-9、VEGF 和 TNFα 的表达。
结论：白藜芦醇限制了弹性蛋白酶诱导的 AAA 中单核细胞依赖性炎症反应、巨噬细胞分化和主动脉管腔扩大。这些数据表明，白藜芦醇可能在选择的小 AAA 患者中进行测试，以调节与 AAA 进展相关的早期全身和局部炎症反应。
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