期刊
MOLECULAR THERAPY
卷 26, 期 4, 页码 1040-1055出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2018.01.011
关键词
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资金
- Swedish Heart-Lung-Foundation [20120615, 20130664, 20140186]
- Ragnar Soderberg Foundation [M-14/55]
- Karolinska Institute Cardiovascular Program Career Development Grant
- European Research Council (ERC Starting Grant NORVAS)
- German Center for Cardiovascular Research (DZHK)
- Swedish Research Council [K2009-65X-2233-01-3, K2013-65X-06816-30-4, 349-2007-8703]
- Uppdrag Besegra Stroke [P581/2011-123]
- Strategic Cardiovascular Programs of Karolinska Institutet and Stockholm County Council [ALF-2011-0260, ALF-2011-0279]
- Foundation for Strategic Research
- European Commission (CarTarDis, AtheroR-emo, VIA, and AtheroFlux projects)
miRNAs are potential regulators of carotid artery stenosis and concordant vulnerable atherosclerotic plaques. Hence, we analyzed miRNA expression in laser captured micro-dissected fibrous caps of either ruptured or stable plaques (n = 10 each), discovering that miR-21 was significantly downregulated in unstable lesions. To functionally evaluate miR-21 in plaque vulnerability, miR-21 and miR-21/apolipoprotein-E double-deficient mice (Apoe(-/-) miR-21(-/-)) were assessed. miR-21(-/-) mice lacked sufficient smooth muscle cell proliferation in response to carotid ligation injury. When exposing Apoe(-/-) miR-21(-/-) mice to an inducible plaque rupture model, they presented with more atherothrombotic events (93%) compared with miR-21(+/+) Apoe(-/-) mice (57%). We discovered that smooth muscle cell fate in experimentally induced advanced lesions is steered via a REST-miR-21-REST feedback signaling pathway. Furthermore, Apoe(-/-) miR-21(-/-) mice presented with more pronounced atherosclerotic lesions, greater foam cell formation, and substantially higher levels of arterial macrophage infiltration. Local delivery of a miR-21 mimic using ultrasound-targeted microbubbles into carotid plaques rescued the vulnerable plaque rupture phenotype. In the present study, we identify miR-21 as a key modulator of pathologic processes in advanced atherosclerosis. Targeted, lesion site-specific overexpression of miR-21 can stabilize vulnerable plaques.
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