Smooth muscle NADPH oxidase 4 promotes angiotensin II-induced aortic aneurysm and atherosclerosis by regulating osteopontin
Smooth muscle NADPH oxidase 4 promotes angiotensin II-induced aortic aneurysm and atherosclerosis by regulating osteopontin
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平滑肌NADPH氧化酶4通过调节骨桥蛋白促进血管紧张素II诱导的主动脉瘤和动脉粥样硬化
DOI：
10.1016/j.bbadis.2020.165912
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Xiaoyong Tong
中科院分区：
文献类型：
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作者：
Weimin Yu;Li Xiao;Yumei Que;Siqi Li;Lili Chen;Pingping Hu;Rui Xiong;Francesca Seta;Hao Chen;Xiaoyong Tong
背景与目的血管紧张素II （angiotensin II, Ang II）在动物模型中常用来诱导主动脉瘤和动脉粥样硬化。angii上调小鼠主动脉平滑肌细胞（SMCs）中NADPH氧化酶异构体Nox4。然而，平滑肌Nox4是否直接参与Ang ii诱导的主动脉瘤和动脉粥样硬化尚不清楚。方法与结果为了解决这个问题，我们使用了平滑肌特异性Nox4显性阴性（SDN）转基因小鼠，其中Nox4活性被组成性抑制。在非转基因（NTg）小鼠中，Ang II增加了已知与主动脉瘤和动脉粥样硬化有关的蛋白的表达，即骨桥蛋白（OPN）、胶原i型和iii型（Col I&III）、基质金属蛋白酶2 （MMP2）和血管细胞粘附分子1 (VCAM1)，这些蛋白在SDN小鼠中均显著下调。与NTg小鼠相比，Angⅱ诱导的SDN小鼠主动脉旁支动脉瘤数量和大小以及肾动脉和主动脉根动脉粥样硬化病变明显减少，且与OPN表达降低直接相关。在SDN SMCs中补充OPN，增加Col I&III、MMP2和VCAM1的表达，促进SMC的增殖、迁移和炎症。结论数据表明，平滑肌Nox4至少部分通过调控OPN的表达，直接促进了Ang ii诱导的主动脉瘤和动脉粥样硬化的发展。
Background and aimsAngiotensin II (Ang II) is commonly used to induce aortic aneurysm and atherosclerosis in animal models. Ang II upregulates NADPH oxidase isoform Nox4 in aortic smooth muscle cells (SMCs) in mice. However, whether smooth muscle Nox4 is directly involved in Ang II-induced aortic aneurysm and atherosclerosis is unclear.Methods & resultsTo address this, we used smooth muscle-specific Nox4 dominant-negative (SDN) transgenic mice, in which Nox4 activity is constitutively inhibited. In non-transgenic (NTg) mice, Ang II increased the expression of proteins known to contribute to both aortic aneurysm and atherosclerosis, namely osteopontin (OPN), collagen type I&III (Col I&III), matrix metalloproteinase 2 (MMP2), and vascular cell adhesion molecule 1 (VCAM1), which were all significantly downregulated in SDN mice. The number and size of Ang II-induced aorta collateral aneurysms and atherosclerotic lesions in the renal artery and aortic root of SDN mice were significantly decreased compared to NTg mice, and directly correlated with a decrease in OPN expression. Replenishing OPN in SDN SMCs, increased the expression of Col I&III, MMP2, and VCAM1, and promoted SMC proliferation, migration, and inflammation.ConclusionsOur data demonstrate that smooth muscle Nox4 directly promotes the development of Ang II-induced aortic aneurysm and atherosclerosis, at least in part, through regulating OPN expression.