Background and aims

Angiotensin 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 & results

To 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.

Conclusions

Our 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.

中文翻译：

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平滑肌NADPH氧化酶4通过调节骨桥蛋白来促进血管紧张素II诱导的主动脉瘤和动脉粥样硬化。

背景和目标

血管紧张素II（Ang II）通常用于在动物模型中诱发主动脉瘤和动脉粥样硬化。Ang II上调小鼠主动脉平滑肌细胞（SMCs）中的NADPH氧化酶亚型Nox4。但是，尚不清楚平滑肌Nox4是否直接参与Ang II诱导的主动脉瘤和动脉粥样硬化。

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显性负（SDN）转基因小鼠，其中Nox4的活性受到组成性抑制。在非转基因（NTg）小鼠中，Ang II增加了已知有助于主动脉瘤和动脉粥样硬化的蛋白质的表达，即骨桥蛋白（OPN），I＆III型胶原（Col I＆III），基质金属蛋白酶2（MMP2）和血管细胞粘附分子1（VCAM1），它们在SDN小鼠中均显着下调。与NTg小鼠相比，Ang II诱导的SDN小鼠的肾动脉和主动脉根中的主动脉副动脉瘤和动脉粥样硬化病变的数量和大小显着减少，并且与OPN表达的降低直接相关。在SDN SMC中补充OPN，增加了Col I＆III，MMP2和VCAM1的表达，

结论

我们的数据表明，平滑肌Nox4至少部分地通过调节OPN表达直接促进Ang II诱导的主动脉瘤和动脉粥样硬化的发展。