A Novel Mechanism Underlying Inflammatory Smooth Muscle Phenotype in Abdominal Aortic Aneurysm.
A Novel Mechanism Underlying Inflammatory Smooth Muscle Phenotype in Abdominal Aortic Aneurysm.
复制标题
腹主动脉瘤炎性平滑肌表型的新机制。
DOI：
10.1161/circresaha.121.319374
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发表时间：
2021-10-29
影响因子：
20.1
通讯作者：
Chen SY
中科院分区：
文献类型：
--
作者：
Cai D;Sun C;Zhang G;Que X;Fujise K;Weintraub NL;Chen SY
腹主动脉瘤(AAA)是一种永久性和局限性的腹主动脉扩张，可能导致主动脉破裂的致命后果。目前还没有发现有效的药理学方法来限制AAA的进展和破裂。AAA的特点是广泛的主动脉壁基质降解，导致动脉壁重构和最终破裂，其中平滑肌细胞(SMC)表型转变和基质金属蛋白酶(MMP)，尤其是MMP2和MMP9在其中起关键作用。我们先前的研究表明，作用于RNA 1的腺苷脱氨酶(ADAR1)调节SMC表型，这促使我们研究ADAR1是否参与AAA的发生。我们采用血管紧张素II(Ang II)输注载脂蛋白E−/−小鼠模型，结合ADAR1整体和SMC特异性基因敲除，研究ADAR1在腹主动脉形成/夹层形成中的作用。通过主动脉移植来确定血管细胞ADAR1在AAA发展/夹层中的重要性。用原代培养的SMC研究ADAR1对炎性SMC表型和基质金属蛋白酶产生/活性的调节作用。获取患者样本以研究ADAR1表达与人类AAA疾病的相关性。人和小鼠腹主动脉SMC均可诱导ADAR1表达。ADAR1杂合基因敲除可减少血管紧张素转换酶II诱导的载脂蛋白E−/−小鼠的腹主动脉夹层。小鼠主动脉移植表明，血管细胞中的ADAR1是AAA形成所必需的。SMC特异的ADAR1基因敲除减少了实验性AAA的形成/解剖。在机制上，ADAR1与HUR相互作用，增加MMP2和MMP9mRNA的稳定性，导致MMP2水平和活性增加。ADAR1是AAA发生/夹层的新调节因子，因此可能成为阻止AAA生长和破裂的潜在新的治疗靶点。
Abdominal aortic aneurysm (AAA) is a permanent and localized dilatation of abdominal aorta with potentially fatal consequence of aortic rupture. No effective pharmacological approach has been identified to limit AAA progression and rupture. AAA is characterized by extensive aortic wall matrix degradation that contributes to arterial wall remodeling and eventual rupture, in which smooth muscle cell (SMC) phenotypic transition and matrix metalloproteinases (MMP), especially MMP2 and MMP9, play critical roles. Our previous study showed that adenosine deaminases acting on RNA 1 (ADAR1) regulates SMC phenotype, which prompted us to study if ADAR1 is involved in AAA development. We used angiotensin II (Ang II) infusion ApoE−/− mouse model combined with ADAR1 global and SMC-specific knockout to study the role of ADAR1 in AAA formation/dissection. Aortic transplantation was conducted to determine the importance of vascular cell ADAR1 in AAA development/dissection. Primary cultured SMC were used to study how ADAR1 regulates the inflammatory SMC phenotype and MMP production/activity. Patient specimens were obtained to investigate the relevance of ADAR1 expression to human AAA disease. ADAR1 was induced in abdominal aortic SMC in both mouse and human AAA tissues. Heterozygous knockout of ADAR1 diminished the Ang II-induced AAA/dissection in ApoE−/− mice. Mouse aortic transplantation showed that ADAR1 in vascular cells was essential for AAA formation. SMC-specific ADAR1 knockout reduced experimental AAA formation/dissection. Mechanistically, ADAR1 interacted with HuR to increase the stability of MMP2 and MMP9 mRNA, leading to increased MMP levels and activities. ADAR1 is novel regulator of AAA development/dissection, and thus may represent a potentially new therapeutic target to hinder AAA growth and rupture.