Apolipoprotein-A1 transports and regulates MMP2 in the blood.

Synthesized in the liver and intestines, apolipoprotein A1 (APOA1) transports cholesterol in high density lipoproteins from atherosclerotic lesions to the liver, protecting against atherosclerotic plaque rupture. Here, we show that proMMP2 (zymogen of matrix metalloproteinase-2) circulates associated with APOA1 in humans and APOA1-expressing mice. This is noteworthy because MMP2 is the most abundant MMP in blood, and MMPs promote atherosclerotic plaque rupture. Artificial intelligence (AlphaFold)-based modeling suggested that APOA1 and MMP2 interact; direct interactions were confirmed using five orthogonal interaction assays, showing that APOA1 binds to MMP2 catalytic and hemopexin-like domains. APOA1 inhibited MMP2 autolysis and allosterically increased MMP2 activity-an effect specifically reproduced by plasma from humans and APOA1-expressing mice but not albumin nor plasma from APOA1 knockout mice. These function-altering interactions with APOA1 may increase MMP2 bioavailability and lay the foundation for future research on how apolipoproteins and MMPs influence atherosclerotic plaque rupture, independently of cholesterol transport.