期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 34, 期 7, 页码 1412-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.113.303134
关键词
abdominal aortic aneurysm; angiotensin II; microRNA; TIMP3
资金
- National Institutes of Health [HL095070, HL114772, HL113451]
- National Heart Lung and Blood Institute of the National Institutes of Health [HHSN268201000043C]
Objective-Abdominal aortic aneurysm (AAA) is characterized as a progressive dilation and degradation of the aortic wall, associated with activation of matrix metalloproteinases (MMPs) and inflammation. Emerging evidence indicates a role for microRNAs (miRNAs) in AAA pathogenesis, but it is unclear whether abdominal aortic endothelial miRNAs play a role in the disease process. We aimed to identify miRNAs in the abdominal aortic endothelium that play a critical role in AAA development. Approach and Results-The mouse model of AAA induced by angiotensin II infusion was used in this study. Through a miRNA array and validation study, we initially identified the murine-specific miR-712 and subsequently its human/murine homolog miR-205 as angiotensin II-induced miRNAs in the abdominal aortic endothelium in vivo and in vitro. Mechanistically, miR-712 stimulated MMP activity in the aortic wall by directly targeting 2 MMP inhibitors: tissue inhibitor of metalloproteinase 3 (TIMP3) and reversion-inducing cysteine-rich protein with kazal motifs (RECK). Silencing of miR-712 and miR-205 by using anti-miR-712 and anti-miR-205, respectively, significantly decreased the aortic MMP activity and inflammation, preventing AAA development in angiotensin II-infused ApoE(-/-) mice. Further, upregulation of 4 angiotensin II-sensitive miRNAs, miR-205, -21, -133b, and -378, identified in this murine study were confirmed in human AAA samples compared with nondiseased control. Conclusions-Our results demonstrate that angiotensin II-sensitive miR-712 and its human homolog miR-205 downregulate TIMP3 and RECK, which in turn stimulate aortic MMP activity and inflammation, leading to AAA development. Targeting these miRNAs may be a novel therapeutic strategy to prevent AAA.
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