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Published on: December 21, 2014
Influence of matrix metalloproteinase-12 on fibrinogen level
Anna Motterle1, Qingzhong Xiao, Stefan Kiechl
1William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Abstract:
In vitro studies have shown that matrix metalloproteinase-12 (MMP12) can degrade fibrinogen, a clotting factor whose level predicts risk of advanced atherosclerosis and myocardial infarction. In this study, we found that mean plasma fibrinogen level was approximately 10-fold higher in MMP12 knockout mice than wildtype mice (p=0.0006). Differential allelic expression analysis of human MMP12 gene polymorphism rs17368582 in human vascular tissues showed an allele-specific effect on MMP12 expression, with one allele (T) having 1.6 fold higher expression level than the other allele (C) (p=0.0006). In a population cohort, we found that individuals homozygous for the MMP12 low expression allele had higher plasma fibrinogen levels (2.95 mg/mL compared with 2.61 mg/mL in other individuals, p=0.029) and increased risk of advanced atherosclerosis [odds ratio 6.3 (95% CI 1.9-20.8), p=0.003] and myocardial infarction [hazard ratio 5.6 (95% CI 1.7-18.3), p=0.005]. In summary, our study in mouse and humans provides in vivo evidence of an effect of MMP12 on fibrinogen level.
Insights
Matrix metalloproteinase-12 (MMP12) influences fibrinogen levels. Lower MMP12 activity correlates with higher fibrinogen, increasing risks for atherosclerosis and myocardial infarction in humans.
Area of Science:
- Cardiovascular Biology
- Enzymology
- Genetics
Background:
- Matrix metalloproteinase-12 (MMP12) is known to degrade fibrinogen in vitro.
- Elevated fibrinogen levels are associated with increased risk of advanced atherosclerosis and myocardial infarction.
Purpose of the Study:
- To investigate the in vivo role of MMP12 in regulating plasma fibrinogen levels.
- To examine the association between MMP12 genetic variation, fibrinogen levels, and cardiovascular disease risk in humans.
Main Methods:
- MMP12 knockout mice were used to assess plasma fibrinogen levels compared to wildtype mice.
- Differential allelic expression analysis of human MMP12 polymorphism rs17368582 was performed in vascular tissues.
- A population cohort was analyzed to correlate MMP12 genotype with plasma fibrinogen, atherosclerosis, and myocardial infarction risk.
Main Results:
- MMP12 knockout mice exhibited approximately 10-fold higher plasma fibrinogen levels than wildtype mice.
- Human MMP12 polymorphism rs17368582 showed allele-specific expression, with the T allele having 1.6-fold higher expression than the C allele.
- Individuals homozygous for the low-expression MMP12 allele had higher fibrinogen levels and significantly increased risks of advanced atherosclerosis and myocardial infarction.
Conclusions:
- This study provides in vivo evidence in both mice and humans that MMP12 affects plasma fibrinogen levels.
- MMP12 activity and its genetic variations are linked to fibrinogen regulation and cardiovascular disease risk.
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