当前位置： SCI文献检索 > CIRCULATION RESEARCH期刊下所有文献 > A novel mouse model of atherosclerotic plaque instability for drug testing and mechanistic/therapeutic discoveries using gene and microRNA expression profiling.

A novel mouse model of atherosclerotic plaque instability for drug testing and mechanistic/therapeutic discoveries using gene and microRNA expression profiling.

Abstract：

RATIONALE:The high morbidity/mortality of atherosclerosis is typically precipitated by plaque rupture and consequent thrombosis. However, research on underlying mechanisms and therapeutic approaches is limited by the lack of animal models that reproduce plaque instability observed in humans. OBJECTIVE:Development and use of a mouse model of plaque rupture that reflects the end stage of human atherosclerosis. METHODS AND RESULTS:On the basis of flow measurements and computational fluid dynamics, we applied a tandem stenosis to the carotid artery of apolipoprotein E-deficient mice on high-fat diet. At 7 weeks postoperatively, we observed intraplaque hemorrhage in ≈50% of mice, as well as disruption of fibrous caps, intraluminal thrombosis, neovascularization, and further characteristics typically seen in human unstable plaques. Administration of atorvastatin was associated with plaque stabilization and downregulation of monocyte chemoattractant protein-1 and ubiquitin. Microarray profiling of mRNA and microRNA (miR) and, in particular, its combined analysis demonstrated major differences in the hierarchical clustering of genes and miRs among nonatherosclerotic arteries, stable, and unstable plaques and allows the identification of distinct genes/miRs, potentially representing novel therapeutic targets for plaque stabilization. The feasibility of the described animal model as a discovery tool was established in a pilot approach, identifying a disintegrin and metalloprotease with thrombospondin motifs 4 (ADAMTS4) and miR-322 as potential pathogenic factors of plaque instability in mice and validated in human plaques. CONCLUSIONS:The newly described mouse model reflects human atherosclerotic plaque instability and represents a discovery tool toward the development and testing of therapeutic strategies aimed at preventing plaque rupture. Distinctly expressed genes and miRs can be linked to plaque instability.

journal_name

Circ Res

journal_title

Circulation research

authors

Chen YC,Bui AV,Diesch J,Manasseh R,Hausding C,Rivera J,Haviv I,Agrotis A,Htun NM,Jowett J,Hagemeyer CE,Hannan RD,Bobik A,Peter K

doi

10.1161/CIRCRESAHA.113.301562

subject

Has Abstract

pub_date

2013-07-19 00:00:00

pages

252-65

issue

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.113.301562

journal_volume

113

pub_type

杂志文章

在线工具

A novel mouse model of atherosclerotic plaque instability for drug testing and mechanistic/therapeutic discoveries using gene and microRNA expression profiling.