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Caveolin-1 inhibits matrix metalloproteinase-2 activity in the heart
A K Chow1, J Cena, A F El-Yazbi
1Department of Pediatrics, Cardiovascular Research Group, University of Alberta, 4-62 Heritage Medical Research Centre, Edmonton, Alberta, Canada T6G 2S2.
Abstract:
Apart from its ability to degrade extracellular matrix proteins, matrix metalloproteinase-2 (MMP-2) was recently revealed to have targets and actions within the cardiac myocyte. The localization of MMP-2 in caveolae of endothelial cells suggests that caveolin-1 (Cav-1) may play a role in regulating MMP-2. The caveolin scaffolding domain (CSD) of Cav-1 regulates several proteins including those involved with signaling cascades. Whether Cav-1 is responsible for regulating MMP-2 in the heart is unknown. Hearts from Cav-1(-/-) or Cav-1(+/+) mice were isolated and heart extracts or lipid raft enriched membrane fractions were prepared. MMP-2 activity in Cav-1(-/-) hearts was markedly enhanced when compared with Cav-1(+/+) hearts with no changes in MMP-2 protein levels between groups. In contrast, MMP-2 activity and protein level were greatly reduced in lipid raft enriched fractions of Cav-1(-/-) hearts. Purified CSD inhibited MMP-2 activity in a concentration-dependent manner as assessed using an in vitro degradation assay with a fluorogenic MMP-2 substrate (OmniMMP). These data suggest that Cav-1 plays a role in regulating MMP-2 activity. Cav-1 may thus be a novel mechanism to regulate MMP-2 activity in the heart.
Insights
Caveolin-1 (Cav-1) regulates matrix metalloproteinase-2 (MMP-2) activity in cardiac myocytes. Loss of Cav-1 enhances MMP-2 activity, suggesting Cav-1 is a novel regulator of MMP-2 in the heart.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Protein Regulation
Background:
- Matrix metalloproteinase-2 (MMP-2) has intracellular roles in cardiac myocytes.
- Caveolin-1 (Cav-1) localizes to caveolae and may regulate MMP-2.
- The role of Cav-1 in cardiac MMP-2 regulation is currently unknown.
Purpose of the Study:
- To investigate the role of Caveolin-1 (Cav-1) in regulating matrix metalloproteinase-2 (MMP-2) activity within the heart.
- To determine if Cav-1 influences MMP-2 levels or activity in cardiac tissue.
Main Methods:
- Isolated hearts from Cav-1 knockout (Cav-1(-/-)) and wild-type (Cav-1(+/+)) mice.
- Preparation of heart extracts and lipid raft-enriched membrane fractions.
- Assay of MMP-2 activity and protein levels; in vitro inhibition assay using purified Cav-1 scaffolding domain (CSD).
Main Results:
- MMP-2 activity was significantly increased in Cav-1(-/-) hearts compared to Cav-1(+/+) hearts, with no change in protein levels.
- MMP-2 activity and protein levels were reduced in lipid raft fractions from Cav-1(-/-) hearts.
- Purified CSD inhibited MMP-2 activity in a concentration-dependent manner in vitro.
Conclusions:
- Caveolin-1 (Cav-1) plays a significant role in regulating matrix metalloproteinase-2 (MMP-2) activity in the heart.
- Cav-1 may represent a novel mechanism for controlling MMP-2 activity in cardiac myocytes.
- The caveolin scaffolding domain (CSD) appears to directly inhibit MMP-2 activity.
