Endothelial cell-specific reactive oxygen species production increases susceptibility to aortic dissection.
Endothelial cell-specific reactive oxygen species production increases susceptibility to aortic dissection.
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DOI：
10.1161/circulationaha.113.005062
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发表时间：
2014-06-24
期刊：
影响因子：
37.8
通讯作者：
Channon KM
中科院分区：
文献类型：
--
作者：
Fan LM;Douglas G;Bendall JK;McNeill E;Crabtree MJ;Hale AB;Mai A;Li JM;McAteer MA;Schneider JE;Choudhury RP;Channon KM
整个血管壁活性氧 (ROS) 产生的增加是心血管疾病状态的一个特征，但由于我们对特定血管细胞 ROS 在疾病发病机制中的作用和贡献的不完全了解，治疗策略仍然受到限制。为了研究内皮细胞（EC）ROS在结构性血管疾病发展中的具体作用，我们构建了内皮特异性Nox2过表达的小鼠模型，并测试了输注血管紧张素II（Ang II）后对主动脉夹层的易感性。 Nox2 转基因小鼠中内皮 ROS 产生的特定增加足以引起 Ang II 介导的主动脉夹层，而这在野生型小鼠中从未观察到。 Nox2转基因主动脉增加了内皮ROS的产生、内皮血管细胞粘附分子1的表达、基质金属蛋白酶活性和CD45+炎症细胞浸润。与野生型对照相比，Nox2 转基因 EC 的条件培养基通过分泌亲环蛋白 A (CypA) 诱导血管平滑肌细胞中更高的 Erk1/2 磷酸化。 Nox2 转基因 EC（但不是血管平滑肌细胞）和主动脉在基线和对 Ang II 刺激的反应中都有更多的 CypA 分泌。 EC 中 CypA 的敲低消除了 EC 条件培养基赋予的血管平滑肌细胞 Erk1/2 磷酸化的增加，并且与 CypA 预孵育增强了 Ang II 诱导的血管平滑肌细胞 ROS 产生。这些发现表明 EC 衍生的 ROS 在确定主动脉壁对 Ang II 介导的主动脉夹层的易感性方面发挥着关键作用。 EC 分泌的 ROS 依赖性 CypA 是一种重要的信号传导机制，EC ROS 通过该机制调节主动脉壁结构成分对主动脉夹层的易感性。
Increased production of reactive oxygen species (ROS) throughout the vascular wall is a feature of cardiovascular disease states, but therapeutic strategies remain limited by our incomplete understanding of the role and contribution of specific vascular cell ROS to disease pathogenesis. To investigate the specific role of endothelial cell (EC) ROS in the development of structural vascular disease, we generated a mouse model of endothelium-specific Nox2 overexpression and tested the susceptibility to aortic dissection after angiotensin II (Ang II) infusion. A specific increase in endothelial ROS production in Nox2 transgenic mice was sufficient to cause Ang II–mediated aortic dissection, which was never observed in wild-type mice. Nox2 transgenic aortas had increased endothelial ROS production, endothelial vascular cell adhesion molecule-1 expression, matrix metalloproteinase activity, and CD45+ inflammatory cell infiltration. Conditioned media from Nox2 transgenic ECs induced greater Erk1/2 phosphorylation in vascular smooth muscle cells compared with wild-type controls through secreted cyclophilin A (CypA). Nox2 transgenic ECs (but not vascular smooth muscle cells) and aortas had greater secretion of CypA both at baseline and in response to Ang II stimulation. Knockdown of CypA in ECs abolished the increase in vascular smooth muscle cell Erk1/2 phosphorylation conferred by EC conditioned media, and preincubation with CypA augmented Ang II–induced vascular smooth muscle cell ROS production. These findings demonstrate a pivotal role for EC-derived ROS in the determination of the susceptibility of the aortic wall to Ang II–mediated aortic dissection. ROS-dependent CypA secretion by ECs is an important signaling mechanism through which EC ROS regulate susceptibility of structural components of the aortic wall to aortic dissection.