A Novel Mouse Model of Atherosclerotic Plaque Instability for Drug Testing and Mechanistic/Therapeutic Discoveries Using Gene and microRNA Expression Profiling
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 utilization of a mouse model of plaque rupture that reflects the end stage of human atherosclerosis.
Methods and Results: Based on flow measurements and computational fluid dynamics, we applied a tandem stenosis to the carotid artery of ApoE-/- mice on high fat diet. At 7 weeks postoperatively, we observed intraplaque hemorrhage in ~50% of mice, as well as disruption of fibrous caps, intra¬luminal thrombosis, neovascularization and further characteristics typically seen in human unstable plaques. Administration of atorvastatin was associated with plaque stabilization and down regulation of MCP-1 and ubiquitin. Microarray profiling of mRNA and microRNA and in particular its combined analysis demon¬strated major differences in the hierarchical clustering of genes and microRNAs between non-atherosclerotic arteries, stable and unstable plaques and allows the identification of distinct genes/microRNAs, 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 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 towards the development and testing of therapeutic strategies aimed at preventing plaque rupture. Distinctly expressed genes and microRNAs can be linked to plaque instability.
- plaque instability
- mouse model
- gene expression profiling
- microRNA profiling
- animal model cardiovascular disease
- plaque rupture
- Received April 20, 2013.
- Revision received May 30, 2013.
- Accepted June 7, 2013.