Matrix metalloproteinase 8 degrades apolipoprotein A-I and reduces its cholesterol efflux capacity

Area of Science:

• Biochemistry
• Cardiovascular Biology
• Enzymology

Background:

• Atherosclerotic lesions contain matrix metalloproteinase-8 (MMP-8).
• Apolipoprotein A-I (apoA-I) is crucial for high-density lipoprotein (HDL) structure and antiatherogenic function.
• The role of MMP-8 in modifying apoA-I and its impact on reverse cholesterol transport is unclear.

Purpose of the Study:

• To investigate MMP-8's effect on apoA-I structure and function.
• To assess MMP-8's impact on cholesterol efflux capacity.
• To analyze serum lipid profiles and HDL characteristics in MMP-8-deficient mice.

Main Methods:

• Incubation of purified apoA-I and HDL with activated MMP-8.
• Mass spectrometry to identify apoA-I cleavage sites.
• In vitro cholesterol efflux assays using THP-1 macrophages.
• Analysis of serum lipids, apoA-I levels, and cholesterol efflux in MMP-8-deficient and wild-type mice.

Main Results:

• MMP-8 cleaved apoA-I into 22 kDa and 25 kDa fragments, primarily at the carboxyl-terminal region.
• MMP-8 treatment significantly reduced apoA-I and HDL's cholesterol efflux capacity by up to 84%.
• Doxycycline inhibited MMP-8-mediated apoA-I cleavage and reduced cholesterol efflux capacity.
• MMP-8-deficient mice exhibited lower serum triglycerides and larger HDL particles compared to wild-type mice.

Conclusions:

• Proteolytic modification of apoA-I by MMP-8 impairs reverse cholesterol transport.
• This impairment may contribute to cholesterol accumulation in atherosclerotic plaques.
• Inhibition of MMPs, potentially with doxycycline, could offer a therapeutic strategy against atherosclerotic vascular diseases.