Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms.
Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms.
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炎症和氧化应激是许多疾病的致病介质，但治疗目标仍然难以捉摸。在血管系统中，腹主动脉瘤(AAA)的形成与炎症和基质降解密切相关。亲环素A(CyclophinA，CyPA)由Ppia编码，在血管平滑肌细胞(VSMC)中高表达，受活性氧(ROS)刺激而分泌，促进炎症反应。使用血管紧张素II(AngII)诱导的apoE−/−小鼠AA模型，我们发现与apoE−/−Ppia+/+小鼠相比，apoE−/−小鼠完全不受AngII诱导的aAA形成的影响。APOE−/−Ppia−/−小鼠表现出炎性细胞因子表达减少、弹力板降解和主动脉扩张。这些特征不会因Ppia+/+小鼠的骨髓细胞重建而改变。机制研究表明，VSMC来源的细胞内和细胞外的CyPA是产生ROS和激活基质金属蛋白酶-2所必需的。这些数据定义了CyPA在AAA形成中的新作用，并表明CyPA是心血管治疗的新靶点。
Inflammation and oxidative stress are pathogenic mediators of many diseases, but therapeutic targets remain elusive. In the vasculature, abdominal aortic aneurysm (AAA) formation critically involves inflammaton and matrix degradation. Cyclophilin A (CyPA, encoded by Ppia) is highly expressed in vascular smooth muscle cells (VSMC), is secreted in response to reactive oxygen species (ROS), and promotes inflammation. Using the angiotensin II (AngII)-induced AAA model in Apoe−/− mice, we show that Apoe−/−Ppia−/− mice were completely protected from AngII–induced AAA formation, in contrast to Apoe−/−Ppia+/+ mice. Apoe−/−Ppia−/− mice showed decreased inflammatory cytokine expression, elastic lamina degradation, and aortic expansion. These features were not altered by reconstitution of bone marrow cells from Ppia+/+ mice. Mechanistic studies demonstrated that VSMC-derived intracellular and extracellular CyPA were required for ROS generation and matrix metalloproteinase-2 activation. These data define a novel role for CyPA in AAA formation and suggest CyPA is a new target for cardiovascular therapies.
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影响因子：
15.9
作者：
Bruemmer, D;Collins, AR;Hsueh, WA
通讯作者：
Hsueh, WA
影响因子：
15.9
作者：
Longo, GM;Xiong, WF;Baxter, BT
通讯作者：
Baxter, BT
影响因子：
37.8
作者：
Kunieda, Takeshige;Minamino, Tohru;Komuro, Issei
通讯作者：
Komuro, Issei
DOI：
10.1161/01.atv.0000142806.59283.11
发表时间：
2004-10-01
影响因子：
8.7
作者：
Haug, C;Lenz, C;Bachem, MG
通讯作者：
Bachem, MG
影响因子：
4.8
作者：
Liao, DF;Jin, ZG;Berk, BC
通讯作者：
Berk, BC