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Published on: January 13, 2012
Shear stress-induced MMP1 and PDE2A expressions in coronary atherosclerosis
Insights
Increased wall shear stress (WSS) in coronary atherosclerosis (CAS) elevates matrix metalloproteinases1 (MMP1) and phosphodiesterase-2A (PDE2A) expression. This suggests MMP1 and PDE2A are potential diagnostic and therapeutic targets for CAS.
Area of Science:
- Cardiovascular research
- Biomedical engineering
- Molecular biology
Background:
- Biomechanical stress is crucial in coronary atherosclerosis (CAS) development.
- The precise relationship between mechanical forces and gene expression in CAS is not fully understood.
Purpose of the Study:
- To investigate the link between wall shear stress (WSS) and gene expression in CAS.
- To identify potential molecular targets for CAS diagnosis and treatment.
Main Methods:
- Finite element modeling was used to map WSS in CAS.
- Aortic tissue samples from CAS patients were analyzed for gene expression using GEO datasets.
- Immunofluorescence staining and Western blotting confirmed protein expression and localization.
Main Results:
- Peak WSS was significantly elevated in stenotic CAS vessels.
- Matrix metalloproteinases 1 (MMP1) and phosphodiesterase-2A (PDE2A) showed increased expression in response to WSS.
- MMP1 and PDE2A upregulation was confirmed in various vascular cells and dependent on WSS levels.
Conclusions:
- Elevated WSS in CAS is associated with increased MMP1 and PDE2A expression.
- MMP1 and PDE2A may serve as potential biomarkers and therapeutic targets for CAS.
- Understanding WSS-mediated gene expression offers insights into CAS pathogenesis.
Aim:
Biomechanical stress plays an essential role in coronary atherosclerosis (CAS), however, inter-relations between mechanical conditions and gene expressions remain unclear.
Methods:
We constructed finite element model of CAS to map human wall shear stress (WSS). Biopsy aortic tissue samples were obtained from 3 CAS patients. Gene expression pattern in CAS was analyzed by GEO datasets. Immunofluorescence staining and western blot confirmed protein expression and localization.
Results:
Peak WSS was significantly increased in the vessel stenosis of CAS at 0.25 s (mean 55.1 Pa). Analyses results of GSE76275 showed matrix metalloproteinases1 (MMP1) and phosphodiesterase-2A (PDE2A) up-regulation in endothelial shear responsiveness, which was further validated and localized in vascular endothelial cells, smooth muscle cells and other cells by double immunofluorescence staining. Western blotting assay demonstrated up-regulation of MMP1 and PDE2A expression dependent on the WSS.
Conclusions:
MMP1 and PDE2A up-regulations rely on increased WSS in development and risk of CAS, suggesting that their elevation may be potential target for diagnosis and treatment (Fig. 3, Ref. 28).
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