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Published on: October 12, 2017
Evidence for an exclusive association of matrix metalloproteinase-9 with dysfunctional high-density lipoprotein: a
S Sini1, D Deepa1, S Harikrishnan2
1Department of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala 695011, India.
Insights
Dysfunctional high-density lipoprotein (HDL) is linked to increased matrix metalloproteinase-9 (MMP-9) activity, promoting inflammation and potentially increasing cardiovascular disease risk.
Area of Science:
- Cardiovascular Science
- Lipoprotein Metabolism
- Inflammation Biology
Background:
- High-density lipoprotein (HDL) possesses antiatherogenic functions, but these can be impaired during atherosclerosis and systemic inflammation.
- HDL dysfunction has been observed even in healthy individuals experiencing systemic inflammation.
- Previous research linked dysfunctional HDL to acute-phase proteins.
Purpose of the Study:
- To investigate the association between dysfunctional HDL and pro-inflammatory proteins beyond acute-phase proteins.
- To explore the role of matrix metalloproteinase-9 (MMP-9) in HDL dysfunction.
Main Methods:
- Serum HDL isolated using density gradient ultracentrifugation, PEG precipitation, and electroelution.
- HDL antioxidant property assessed via LDL oxidation assay.
- MMP-9 activity evaluated using gelatin zymography and Western blot.
Main Results:
- Dysfunctional HDL failed to prevent LDL auto-oxidation and enhanced it.
- Enhanced MMP-9 activity was selectively found in dysfunctional HDL, confirmed by Western blot.
- Dysfunctional HDL induced pro-inflammatory responses in monocytes/macrophages (increased TNF-α, decreased IL-10).
- In vitro incubation demonstrated MMP-9's role in HDL dysfunction.
Conclusions:
- A novel association between MMP-9 and dysfunctional HDL was identified.
- MMP-9 contributes to the pro-inflammatory properties of dysfunctional HDL.
- This molecular connection may elevate cardiovascular disease risk in individuals with dysfunctional HDL.
Objective:
High-density lipoprotein is a heterogeneous class of lipoprotein with diverse antiatherogenic functions. However, these antiatherogenic properties of HDL can be compromised in atherosclerotic conditions. We have recently identified dysfunctionality in HDL even among healthy subjects, during systemic inflammation. This study was carried out with the objective of examining whether dysfunctional HDL is associated with pro-inflammatory proteins other than the acute phase proteins as reported earlier.
Methods:
Serum HDL was isolated by three different methods-density gradient ultracentrifugation, PEG precipitation and electroelution. The antioxidant property of HDL was assessed as change in oxidation of LDL based on Dichloro-dihydro-fluorescein diacetate assay. HDL was subjected to gelatin zymography and western blot for assessment of MMP 9 activity.
Results:
Dysfunctional HDL did not prevent the auto-oxidation of LDL. On the contrary the oxidation was enhanced. The zymogram data indicated enhanced MMP-9 activity selectively in dysfunctional HDL, irrespective of HDL isolation methods. This was confirmed by western blot of HDL probed with antibody specific to MMP 9. We also observed that dysfunctional HDL induced inflammatory response in monocyte/macrophages as evidenced by enhanced TNF-α and decreased IL-10 production. Further, invitro incubation of functional HDL with MMP-9 provided direct evidence for the association of MMP-9 with HDL and the role of MMP-9 in HDL dysfunction.
Conclusion:
A remarkable finding in the present study is the previously unrecognized association of MMP-9 with dysfunctional HDL and its proinflammatory property, indicating a novel molecular connection that can enhance the risk of cardiovascular disease in subjects with dysfunctional HDL.
