Year of Publication

2017

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Physiology

First Advisor

Dr. Ming Cui Gong

Abstract

Abdominal aortic aneurysm (AAA) is a devastating condition that occurs primarily among older people with high mortality when a rupture occurs. Currently there is no proven pharmacological therapy for AAA due to poor understanding of the underlying pathogenesis. The brain and muscle transcription factor ARNT-like (Bmal1), which is known to regulate circadian rhythm, has been implicated in vascular pathologies including atherosclerosis and vascular remodeling, but its role in AAA has not been explored.

Vascular smooth muscle is a central player in aneurysm formation and development because it is critical in all three aortic aneurysm hallmark processes including (a) degradation of elastin and extracellular matrix protein, (b) loss of medium layer smooth muscle cells, and (c) intense inflammatory cell infiltration.

Here we report that smooth muscle-selective deletion of brain and muscle Arnt-like protein-1 (Bmal1) potently protected mice from AAA induced by mineralocorticoid receptor (MR) agonist deoxycorticosterone acetate (DOCA) or Angiotensin II (ANG II) in the presence of high salt. Bmal1 was upregulated by DOCA-salt in the aorta. Moreover, deletion of Bmal1 in smooth muscle selectively upregulated tissue inhibitor of metalloproteinase 4 (TIMP4) and also abolished DOCA-salt-induced elastin degradation and matrix metalloproteinase (MMP) activation. Mechanistically, Bmal1, when bound to TIMP4 promoter, suppressed the transcription of the promoter. Taken together, these results reveal an important but previously unexplored role of smooth muscle Bmal1 in DOCA plus salt-induced AAA. We suggest that TIMP4 constitutes a novel therapeutic target for AAA treatment.

Digital Object Identifier (DOI)

https://doi.org/10.13023/ETD.2017.041

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