Deletion of BMAL1 in Smooth Muscle Cells Protects Mice From Abdominal Aortic Aneurysms.

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Deletion of BMAL1 in Smooth Muscle Cells Protects Mice From Abdominal Aortic Aneurysms.
Arterioscler Thromb Vasc Biol. 2018 May;38(5):1063-1075. doi: 10.1161/ATVBAHA.117.310153. Epub 2018 Feb 8.Lutshumba J1Liu S2Zhong Y1Hou TDaugherty A1Lu H1,2Guo Z3,4Gong MC5.

Abstract

OBJECTIVE:

Abdominal aortic aneurysm (AAA) has high mortality rate when ruptured, but currently, there is no proven pharmacological therapy for AAA because of our poor understanding of its pathogenesis. The current study explored a novel role of smooth muscle cell (SMC) BMAL1 (brain and muscle Arnt-like protein-1)-a transcription factor known to regulate circadian rhythm-in AAA development.

APPROACH AND RESULTS:

SMC-selective deletion of BMAL1 potently protected mice from AAA induced by (1) MR (mineralocorticoid receptor) agonist deoxycorticosterone acetate or aldosterone plus high salt intake and (2) angiotensin II infusion in hypercholesterolemia mice. Aortic BMAL1 was upregulated by deoxycorticosterone acetate-salt, and deletion of BMAL1 in SMCs selectively upregulated TIMP4 (tissue inhibitor of metalloproteinase 4) and suppressed deoxycorticosterone acetate-salt-induced MMP (matrix metalloproteinase) activation and elastin breakages. Moreover, BMAL1 bound to the Timp4 promoter and suppressed Timp4 transcription.

CONCLUSIONS:

These results reveal an important, but previously unexplored, role of SMC BMAL1 in AAA. Moreover, these results identify TIMP4 as a novel target of BMAL1, which may mediate the AAA protective effect of SMC BMAL1 deletion.

KEYWORDS:

ARNTL transcription factor; aortic aneurysm, abdominal; metalloproteases; mice; muscle, smooth, vascular; receptors, mineralocorticoid

PMID: 29437576
PMCID: PMC5920729
DOI: 10.1161/ATVBAHA.117.310153