TY - JOUR
T1 - A novel mouse model of atherosclerotic plaque instability for drug testing and mechanistic/therapeutic discoveries using gene and microRNA expression profiling
AU - Chen, Yung Chih
AU - Bui, Anh Viet
AU - Diesch, Jeannine
AU - Manasseh, Richard
AU - Hausding, Christian
AU - Rivera, Jennifer
AU - Haviv, Izhak
AU - Agrotis, Alex
AU - Htun, Nay Min
AU - Jowett, Jeremy
AU - Hagemeyer, Christoph Eugen
AU - Hannan, Ross D.
AU - Bobik, Alex
AU - Peter, Karlheinz
PY - 2013/7/19
Y1 - 2013/7/19
N2 - 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.
AB - 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.
KW - Acute myocardial infarction
KW - Angiogenesis
KW - Animal models of human disease
KW - Arterial thrombosis
KW - Atherosclerosis
KW - Gene expression profiling
KW - Inflammation
KW - MicroRNA profiling
KW - Plaque rupture
UR - http://www.scopus.com/inward/record.url?scp=84880773545&partnerID=8YFLogxK
U2 - 10.1161/circresaha.113.301562
DO - 10.1161/circresaha.113.301562
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C2 - 23748430
AN - SCOPUS:84880773545
SN - 0009-7330
VL - 113
SP - 252
EP - 265
JO - Circulation Research
JF - Circulation Research
IS - 3
ER -