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Published on: June 29, 2015
Favine/CCDC3 deficiency accelerated atherosclerosis and thrombus formation is associated with decreased MEF2C-KLF2
Sachiko Kobayashi1, Shunbun Kita1,2, Daisuke Okuzaki3
1Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Abstract:
Currently, no mouse models manifest calcification and thrombus formation, which is frequently associated with human atherosclerosis. We demonstrated that lack of Favine/CCDC3 in apoE knockout mice accelerated atherosclerosis accompanied by large cholesterol crystals and calcification, and also promoted thrombus formation in the left ventricle and arteries. Circulating Favine was detectable in WT mouse plasma. RNA-sequencing analysis of aortae in DKO mice showed similar gene expression patterns of human atherosclerosis with unstable and vulnerable plaques. Importantly, human FAVINE mRNA expressions were lower in atheroma plaque than in adjacent intact aortic tissue and decreased with the progression of atherosclerosis. Pathway analysis of aortae in DKO mice suggested the decrease of the MEF2C-KLF2-mediated transcriptional pathway. Favine insufficiency and its attenuated downstream pathways may increase atherosclerosis progression with calcification and thrombus, which have not previously been fully modeled in experimental animals. Favine and its downstream pathways may have therapeutic potential for atherosclerosis.
Insights
Mice lacking Favine/CCDC3 showed accelerated atherosclerosis, including calcification and thrombus formation. This finding offers a new model for studying atherosclerosis and highlights Favine
Area of Science:
- Cardiovascular Biology
- Molecular Pathology
- Atherosclerosis Research
Background:
- Atherosclerosis in humans often involves calcification and thrombus formation.
- Existing mouse models do not fully replicate these key pathological features.
- Favine/CCDC3's role in atherosclerosis is not well understood.
Purpose of the Study:
- To investigate the role of Favine/CCDC3 in atherosclerosis development.
- To establish a novel mouse model exhibiting calcification and thrombus formation.
- To explore potential therapeutic targets for atherosclerosis.
Main Methods:
- Utilized apoE knockout mice lacking Favine/CCDC3 (DKO mice).
- Analyzed atherosclerotic plaque characteristics, including cholesterol crystals and calcification.
- Performed RNA-sequencing on aortae to examine gene expression patterns.
- Investigated the MEF2C-KLF2-mediated transcriptional pathway.
Main Results:
- DKO mice exhibited accelerated atherosclerosis with significant calcification and thrombus formation.
- RNA-sequencing revealed gene expression patterns similar to human atherosclerosis, indicating plaque vulnerability.
- Human FAVINE mRNA levels were reduced in atherosclerotic plaques and decreased with disease progression.
- Pathway analysis indicated downregulation of the MEF2C-KLF2 pathway in DKO mice.
Conclusions:
- Favine/CCDC3 deficiency accelerates atherosclerosis, promoting calcification and thrombus formation in a novel mouse model.
- Reduced Favine and impaired downstream pathways contribute to atherosclerosis progression.
- Favine and its associated pathways represent potential therapeutic targets for atherosclerosis.
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