Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice
Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice
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DOI：
10.1161/circulationaha.105.607168
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发表时间：
2006-08-01
期刊：
影响因子：
37.8
通讯作者：
Weintraub, Neal L.
中科院分区：
文献类型：
--
作者：
Thomas, Manesh;Gavrila, Dan;Weintraub, Neal L.
背景-血管紧张素II （Ang II）通过刺激NADPH氧化酶活性，导致超氧化物（O-2(-)）的形成增加，从而参与血管病理。我们报道了O-2（-）水平、NADPH氧化酶活性和NADPH氧化酶p47（phox）亚基的表达在人腹主动脉瘤（AAAs）中升高。在这里，我们验证了p47phox的缺失会减弱Ang II输注apoE（-/-）小鼠的氧化应激和AAA形成的假设。方法与结果-雄性apoE（-/-）和apoE(-/-) p47（phox-/-）小鼠给予生理盐水或Ang II （1000 ng中心点kg（-1）中心点min(-1)）输注28 d，测定腹主动脉重量和最大直径。检查主动脉组织和血液中动脉瘤疾病和氧化应激的参数。在90%的apoE（-/-）小鼠和16%的apoE(-/-) p47（phox-/-）小鼠中，Ang II输注诱导AAAs （P < 0.05）。与apoE（-/-）小鼠相比，apoE(-/-) p47（phox-/-）小鼠腹主动脉重（14.1 +/- 3.2 vs 35.6 +/- 9.0 mg）、最大主动脉直径（1.5 +/- 0.2 vs 2.4 +/- 0.4 mm）、主动脉NADPH氧化酶活性和氧化应激参数均降低（P < 0.05）。此外，与apoE（-/-）小鼠相比，apoE(-/-) p47（phox-/-）小鼠主动脉巨噬细胞浸润和基质金属蛋白酶-2活性降低。p47phox的缺失减弱了对angii的压力反应；然而，苯肾上腺素与Ang II的共输注恢复了Ang II的升压反应，并没有改变p47phox缺失对AAA形成的保护作用。结论- p47phox的缺失减弱了Ang II诱导的apoE（-/-）小鼠AAA的形成，表明NADPH氧化酶在该模型中AAA的形成中起关键作用。
Background - Angiotensin II (Ang II) contributes to vascular pathology in part by stimulating NADPH oxidase activity, leading to increased formation of superoxide (O-2(-)). We reported that O-2(-) levels, NADPH oxidase activity, and expression of the p47(phox) subunit of NADPH oxidase are increased in human abdominal aortic aneurysms (AAAs). Here, we tested the hypothesis that deletion of p47phox will attenuate oxidative stress and AAA formation in Ang II - infused apoE(-/-) mice.Methods and Results - Male apoE(-/-) and apoE(-/-) p47(phox-/-) mice received saline or Ang II (1000 ng center dot kg(-1) center dot min(-1)) infusion for 28 days, after which abdominal aortic weight and maximal diameter were determined. Aortic tissues and blood were examined for parameters of aneurysmal disease and oxidative stress. Ang II infusion induced AAAs in 90% of apoE(-/-) versus 16% of apoE(-/-) p47(phox-/-) mice (P < 0.05). Abdominal aortic weight (14.1 +/- 3.2 versus 35.6 +/- 9.0 mg), maximal aortic diameter (1.5 +/- 0.2 versus 2.4 +/- 0.4 mm), aortic NADPH oxidase activity, and parameters of oxidative stress were reduced in apoE(-/-) p47(phox-/-) mice compared with apoE(-/-) mice (P < 0.05). In addition, aortic macrophage infiltration and matrix metalloproteinase-2 activity were reduced in apoE(-/-) p47(phox-/-) mice compared with apoE(-/-) mice. Deletion of p47phox attenuated the pressor response to Ang II; however, coinfusion of phenylephrine with Ang II, which restored the Ang II pressor response, did not alter the protective effects of p47phox deletion on AAA formation.Conclusions - Deletion of p47phox attenuates Ang II - induced AAA formation in apoE(-/-) mice, suggesting that NADPH oxidase plays a critical role in AAA formation in this model.