Cytochrome P450 1B1 Contributes to the Development of Angiotensin II-Induced Aortic Aneurysm in Male Apoe(-/-) Mice.
Cytochrome P450 1B1 Contributes to the Development of Angiotensin II-Induced Aortic Aneurysm in Male Apoe(-/-) Mice.
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DOI：
10.1016/j.ajpath.2016.04.005
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发表时间：
2016-08
期刊：
影响因子：
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通讯作者：
S. Thirunavukkarasu;N. Khan;C. Song;Hafiz U Ghafoor;D. Brand;F. Gonzalez;K. Malik
中科院分区：
文献类型：
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作者：
S. Thirunavukkarasu;N. Khan;C. Song;Hafiz U Ghafoor;D. Brand;F. Gonzalez;K. Malik
细胞色素P450 (CYP) 1B1与血管平滑肌细胞迁移、增殖和高血压有关。我们评估了CYP1B1对血管紧张素（Ang） ii诱导的腹主动脉瘤（AAA）的贡献。雄性apoe−/−/Cyp1b1+/+和apoe−/−/Cyp1b1−/−小鼠分别注射Ang II或其载体4周；另一组apoe−/−/Cyp1b1+/+小鼠每3天共给予Cyp1b1抑制剂2,3 ',4,5 ' -四甲基二苯乙烯（TMS），连续4周。在注射Ang II的第28天，采用超声和活体游标卡尺对AAAs进行分析，并对小鼠实施安乐死，收获组织。Ang II在apoe−/−/Cyp1b1+/+小鼠中产生AAAs；经TMS处理的小鼠或apoe−/−/Cyp1b1−/−小鼠的AAAs减少。Ang II增强巨噬细胞、T细胞和血小板的浸润，增加血小板源性生长因子D、Pdgfrb、Itga2和基质金属蛋白酶2和9在主动脉病变中的表达；这些变化在经TMS处理的小鼠和inApoe−/−/Cyp1b1−/−小鼠中被抑制。氧化应激导致主动脉病变组织中环氧合酶-2的表达。这些影响在用TMS处理的apoe−/−/Cyp1b1+/+小鼠和用超氧化物清除剂4-羟基-2,2,6,6-四甲基哌啶-1-氧同时处理的inApoe−/−/Cyp1b1+/+小鼠中最小化。CYP1B1可能通过增强氧化应激和相关信号事件，促进了Ang ii诱导的小鼠AAA和相关致病事件的发展。因此，CYP1B1可作为男性AAA治疗药物的靶点。
Cytochrome P450 (CYP) 1B1 is implicated in vascular smooth muscle cell migration, proliferation, and hypertension. We assessed the contribution of CYP1B1 to angiotensin (Ang) II–induced abdominal aortic aneurysm (AAA). MaleApoe−/−/Cyp1b1+/+andApoe−/−/Cyp1b1−/−mice were infused with Ang II or its vehicle for 4 weeks; another group ofApoe−/−/Cyp1b1+/+mice was coadministered the CYP1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene (TMS) every third day for 4 weeks. On day 28 of Ang II infusion, AAAs were analyzed by ultrasound andex vivoby Vernier calipers, mice were euthanized, and tissues were harvested. Ang II produced AAAs inApoe−/−/Cyp1b1+/+mice; mice treated with TMS orApoe−/−/Cyp1b1−/−mice had reduced AAAs. Ang II enhanced infiltration of macrophages, T cells, and platelets and increased platelet-derived growth factor D,Pdgfrb,Itga2, and matrix metalloproteinases 2 and 9 expression in aortic lesions; these changes were inhibited in mice treated with TMS and inApoe−/−/Cyp1b1−/−mice. Oxidative stress resulted in cyclooxygenase-2 expression in aortic lesions. These effects were minimized inApoe−/−/Cyp1b1+/+mice treated with TMS and inApoe−/−/Cyp1b1−/−mice and by concurrent treatment with the superoxide scavenger 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl. CYP1B1 contributed to the development of Ang II–induced AAA and associated pathogenic events in mice, likely by enhancing oxidative stress and associated signaling events. Thus, CYP1B1 may serve as a target for therapeutic agents for AAA in males.