CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice
CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice
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CYP2J2 过表达会增加小鼠的 EET 并预防血管紧张素 II 诱导的腹主动脉瘤
DOI：
10.1194/jlr.m036533
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发表时间：
2013-05-01
影响因子：
6.5
通讯作者：
Wang, Dao Wen
中科院分区：
文献类型：
--
作者：
Cai, Zhejun;Zhao, Gang;Wang, Dao Wen
细胞色素P450环氧合酶2 J2（CYP 2 J2）代谢花生四烯酸形成环氧二十碳三烯酸（E3），其对心血管系统具有多种有益作用。然而，是否通过体内CYP 2 J2过表达增加雌二醇的产生可以预防腹主动脉瘤（AAA）仍然未知。在这里，我们研究了重组腺相关病毒（rAAV）介导的CYP 2 J2过表达对血管紧张素（Ang）II诱导的AAA在apoE缺陷小鼠的影响。rAAV-CYP 2 J2递送导致主动脉CYP 2 J2的丰富表达和增加的Ehrs产生。研究表明，CYP 2 J2过表达减弱了基质金属蛋白酶的表达和活性、弹性蛋白降解和AAA形成，这与主动脉炎症和巨噬细胞浸润减少有关。在培养的血管平滑肌细胞（VSMCs）中，rAAV介导的CYP 2 J2过表达和雌二醇显著抑制Ang II诱导的炎性细胞因子表达。此外，在VSMC-巨噬细胞共培养系统中，过表达的CYP 2 J2和Eglutamine抑制Ang II诱导的巨噬细胞迁移。我们进一步指出，这些保护作用介导的过氧化物酶体增殖物激活受体（PPAR）γ激活。综上所述，这些结果提供了rAAV介导的CYP 2 J2过表达预防AAA发展的证据，这可能是通过PPAR γ激活和抗炎作用，这表明增加雌二醇水平可以被认为是预防和治疗AAA的潜在策略。蔡志，G. Zhao，J. Yan，W. Liu，W.冯，B。马湖，加-地杨佳王湖，加-地Tu和D. W.王. CYP 2 J2过表达可增加小鼠中的雌二醇并保护其免受血管紧张素II诱导的腹主动脉瘤。J. Lipid Res. 2013. 54：1448-1456。
Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acids to form epoxyeicosatrienoic acids (EETs), which possess various beneficial effects on the cardiovascular system. However, whether increasing EETs production by CYP2J2 overexpression in vivo could prevent abdominal aortic aneurysm (AAA) remains unknown. Here we investigated the effects of recombinant adeno-associated virus (rAAV)-mediated CYP2J2 overexpression on angiotensin (Ang) II-induced AAA in apoE-deficient mice. rAAV-CYP2J2 delivery led to an abundant aortic CYP2J2 expression and increased EETs generation. It was shown that CYP2J2 overexpression attenuated matrix metalloproteinase expression and activity, elastin degradation, and AAA formation, which was associated with reduced aortic inflammation and macrophage infiltration. In cultured vascular smooth muscle cells (VSMCs), rAAV-mediated CYP2J2 overexpression and EETs markedly suppressed Ang II-induced inflammatory cytokine expression. Moreover, overexpressed CYP2J2 and EETs inhibited Ang II-induced macrophage migration in a VSMC-macrophage coculture system. We further indicated that these protective effects were mediated by peroxisome proliferator-activated receptor (PPAR)gamma activation. Taken together, these results provide evidence that rAAV-mediated CYP2J2 overexpression prevents AAA development which is likely via PPAR gamma activation and anti-inflammatory action, suggesting that increasing EETs levels could be considered as a potential strategy to prevent and treat AAA.-Cai, Z., G. Zhao, J. Yan, W. Liu, W. Feng, B. Ma, L. Yang, J-a. Wang, L. Tu, and D. W. Wang. CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice. J. Lipid Res. 2013. 54: 1448-1456.