Deletion of BMAL1 in Smooth Muscle Cells Protects Mice From Abdominal Aortic Aneurysms.
Deletion of BMAL1 in Smooth Muscle Cells Protects Mice From Abdominal Aortic Aneurysms.
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DOI：
10.1161/atvbaha.117.310153
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Gong MC
中科院分区：
文献类型：
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作者：
Lutshumba J;Liu S;Zhong Y;Hou T;Daugherty A;Lu H;Guo Z;Gong MC
Abdominal aortic aneurysm (AAA) has high mortality rate when ruptured, but currently there is no proven pharmacological therapy for AAA due to our poor understanding of its pathogenesis. The current study explored a novel role of smooth muscle cell Arnt-like protein-1 (BMAL1), a transcription factor known to regulate circadian rhythm, in AAA development. Smooth muscle cell-selective deletion of BMAL1 potently protected mice from AAA induced by 1) mineralocorticoid receptor (MR) agonist deoxycorticosterone acetate (DOCA) or aldosterone (Aldo) when provided with high salt, and 2) angiotensin II (Ang II) infusion in hypercholesterolemia mice. Aortic BMAL1 was upregulated by DOCA-salt, and deletion of BMAL1 in smooth muscle cells selectively upregulated tissue inhibitor of metalloproteinase 4 (TIMP4), suppressed DOCA-salt-induced matrix metalloproteinase (MMP) activation and elastin breakages. Moreover, BMAL1 bound to the Timp4 promoter and suppressed Timp4 transcription. These results reveal an important, but previously unexplored, role of smooth muscle cell BMAL1 in AAA. Moreover, these results identify TIMP4 as a novel target of BMAL1 which may mediate the AAA protective effect of smooth muscle cell BMAL1 deletion.
