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.
|Number of pages||13|
|Journal||Arteriosclerosis, Thrombosis, and Vascular Biology|
|State||Published - 2018|
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health (NIH) grants HL125228 and HL106843 (to M.C. Gong and Z. Guo), Veterans Affairs Merit Award I01 BX002141 (to Z. Guo), NIH Ruth L. Kirschstein National Research Service Award predoctoral fellowship F31HL123315 (to J. Lutshumba), and an Institutional Development Award from the National Institute of General Medical Sciences of the NIH under grant P20GM10352.
© 2018 American Heart Association, Inc.
- ARNTL transcription factor
- Aortic aneurysm
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine