Anxa1 in smooth muscle cells protects against acute aortic dissection.
Anxa1 in smooth muscle cells protects against acute aortic dissection.
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平滑肌细胞中的Anxa1可防止急性主动脉夹层。
DOI：
10.1093/cvr/cvab109
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发表时间：
2021-03
影响因子：
10.8
通讯作者：
Changping Zhou;Zhiyong Lin;Huanhuan Cao;Yue Chen;Jingxuan Li;Xiaofen Zhuang;D. Ma;Liang Ji;Wei Li;Suowen Xu;Bing Pan;Lemin Zheng
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文献类型：
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作者：
Changping Zhou;Zhiyong Lin;Huanhuan Cao;Yue Chen;Jingxuan Li;Xiaofen Zhuang;D. Ma;Liang Ji;Wei Li;Suowen Xu;Bing Pan;Lemin Zheng
目的急性主动脉夹层（AAD）是一种高发病率和高死亡率的危及生命的疾病。以往的研究表明，血管平滑肌细胞（VSMC）表型转换调节血管功能和AAD的进展。然而，是否存在保护AAD进展的内源性信号系统仍然未知。我们的目的是研究Anxa 1在VSMC表型转换和AAD发病机制中的作用。方法和结果我们首先通过免疫组织化学染色评估Anxa 1在对照组主动脉和AAD组织中的表达水平。在小鼠AAD组织中观察到Anxa 1表达的强烈增加。与这些发现一致，micro-CT扫描结果表明，Anxa 1在我们的小鼠模型中的AAD的发展中起作用，Anxa 1的全身性缺陷显著进展AAD。相反，Anxa 1模拟肽Ac 2 -26的给药挽救了Anxa 1-/-小鼠中的AAD表型。转录组学研究揭示了Anxa 1在VSMC表型转换中的新作用，Anxa 1缺陷通过下调JunB/MYL 9通路触发VSMC的合成表型。由此产生的VSMC合成表型引起炎症升高和基质金属蛋白酶（MMPs）产生增加，导致弹性蛋白降解增加。小鼠中VSMC限制性Anxa 1缺陷表型模拟VSMC表型转换和随后的AAD加重。最后，我们在人类AAD主动脉标本中的研究概括了小鼠AAD的关键发现，特别是Anxa 1的减少与VSMC表型转换、炎症加剧和人类AAD中MMP产生增强相关。结论Anxa 1是一种新的内源性防御因子，通过抑制血管平滑肌细胞表型转换来预防急性主动脉夹层，提示Anxa 1信号通路可能是AAD药物治疗的潜在靶点。我们的研究可能会导致急性主动脉夹层药物治疗的范式转变。通过对实验动物模型中AAD发病过程中发生的病理变化的仔细检查，我们证明了VSMC表型转换在AAD的发展中起着至关重要的作用。抑制VSMC表型转换及其对主动脉功能的影响可能是未来治疗的可行方法。为此，我们的研究强调了Anxa 1及其模拟肽Ac 2 -26通过预防VSMC向合成表型的转变在AAD中的保护作用。
AIMS Acute aortic dissection (AAD) is a life-threatening disease with high morbidity and mortality. Previous studies have showed that vascular smooth muscle cell (VSMC) phenotype switching modulates vascular function and AAD progression. However, whether an endogenous signaling system that protects AAD progression exists, remains unknown. Our aim is to investigate the role of Anxa1 in VSMC phenotype switching and the pathogenesis of AAD. METHODS AND RESULTS We first assessed Anxa1 expression levels by immunohistochemical staining in control aorta and AAD tissue from mice. A strong increase of Anxa1 expression was seen in the mouse AAD tissues. In line with these findings, micro-CT scan results indicated that Anxa1 plays a role in the development of AAD in our murine model, with systemic deficiency of Anxa1 markedly progressing AAD. Conversely, administration of Anxa1 mimetic peptide, Ac2-26, rescued the AAD phenotype in Anxa1-/- mice. Transcriptomic studies revealed a novel role for Anxa1 in VSMC phenotype switching, with Anxa1 deficiency triggering the synthetic phenotype of VSMCs via down-regulation of the JunB/MYL9 pathway. The resultant VSMC synthetic phenotype rendered elevated inflammation and enhanced matrix metalloproteinases (MMPs) production, leading to augmented elastin degradation. VSMC-restricted deficiency of Anxa1 in mice phenocopied VSMC phenotype switching and the consequent exacerbation of AAD. Finally, our studies in human AAD aortic specimens recapitulated key findings in murine AAD, specifically that the decrease of Anxa1 is associated with VSMC phenotype switch, heightened inflammation, and enhanced MMP production in human aortas. CONCLUSIONS Our findings demonstrated that Anxa1 is a novel endogenous defender that prevents acute aortic dissection by inhibiting vascular smooth muscle cell phenotype switching, suggesting that Anxa1 signaling may be a potential target for AAD pharmacological therapy. TRANSLATIONAL PERSPECTIVE Our studies herein may lead to a paradigm shift for pharmacologic therapy towards acute aortic dissection. Through careful examination of the pathological changes that occur during AAD onset in experimental animal models, we demonstrated that VSMC phenotype switching plays a critical role in the development of AAD. Inhibition of VSMC phenotype switching and its attendant impacts on aortic function may be a viable approach for future treatment. Toward that end, our studies highlighted the protective benefit of Anxa1 and its mimetic peptide Ac2-26 in AAD through prevention of the switching of VSMC to a synthetic phenotype.