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Published on: June 14, 2017
In vivo matrix metalloproteinase-7 substrates identified in the left ventricle post-myocardial infarction using
Ying Ann Chiao1, Rogelio Zamilpa, Elizabeth F Lopez
1Department of Medicine, Division of Cardiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
Abstract:
Matrix metalloproteinase-7 (MMP-7) deletion has been shown to improve survival after myocardial infarction (MI). MMP-7 has a large array of in vitro substrates, but in vivo substrates for MMP-7 following MI have not been fully identified. Accordingly, we evaluated the infarct regions of wild-type (WT; n = 12) and MMP-7 null (null; n = 10) mice using a proteomic strategy. Seven days post-MI, infarct regions of the left ventricles were excised, homogenized, and protein extracts were analyzed by two-dimensional gel electrophoresis and mass spectrometry. Of 13 spots that showed intensity differences between WT and null, the intensities of eight spots were higher and those of five spots were lower in the null group (p < 0.05). Fibronectin and tenascin-C, known in vitro substrates of MMP-7, were identified in spots that showed lower intensity in the null. Immunoblotting and in vitro cleavage assays confirmed reduced fibronectin and tenascin-C fragment generation in the null, and this effect was restored by exogenous administration of MMP-7. Lower levels of full-length peroxiredoxin-1 and -2 and higher levels of the full-length peroxiredoxin-3 were detected in the null group, suggesting MMP-7 deletion may also indirectly regulate protein levels through nonenzymatic mechanisms. In conclusion, this is the first study to identify fibronectin and tenascin-C as in vivo MMP-7 substrates in the infarcted left ventricle using a proteomic approach.
Insights
Matrix metalloproteinase-7 (MMP-7) deletion improves survival after myocardial infarction (MI). This study identifies fibronectin and tenascin-C as key in vivo MMP-7 substrates in the infarcted heart, revealing new therapeutic targets.
Area of Science:
- Cardiovascular Biology
- Proteomics
- Molecular Medicine
Background:
- Matrix metalloproteinase-7 (MMP-7) deletion enhances survival post-myocardial infarction (MI).
- In vivo substrates of MMP-7 in the infarcted heart remain largely unidentified.
- Understanding MMP-7's in vivo targets is crucial for developing novel therapeutic strategies for MI.
Purpose of the Study:
- To identify novel in vivo substrates of MMP-7 in the left ventricle infarct region post-MI.
- To investigate the role of MMP-7 in protein processing within the infarcted myocardium.
- To compare protein profiles between wild-type (WT) and MMP-7 null mice after MI.
Main Methods:
- Proteomic analysis using two-dimensional gel electrophoresis and mass spectrometry on infarct tissues from WT and MMP-7 null mice 7 days post-MI.
- Immunoblotting and in vitro cleavage assays to validate identified substrates.
- Exogenous MMP-7 administration to confirm its role in substrate cleavage.
Main Results:
- Proteomic analysis revealed significant differences in protein expression between WT and MMP-7 null mice.
- Fibronectin and tenascin-C, known in vitro MMP-7 substrates, were identified in lower abundance in MMP-7 null mice, confirming them as in vivo substrates.
- Reduced fibronectin and tenascin-C fragment generation was observed in MMP-7 null mice, which was restored by exogenous MMP-7.
- MMP-7 deletion also appeared to indirectly regulate peroxiredoxin levels.
Conclusions:
- This study provides the first proteomic evidence identifying fibronectin and tenascin-C as in vivo substrates of MMP-7 in the infarcted left ventricle.
- These findings highlight fibronectin and tenascin-C as potential therapeutic targets for mitigating cardiac damage after MI.
- MMP-7 plays a significant role in post-MI cardiac remodeling through the proteolytic processing of specific extracellular matrix proteins.
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