Sarker Hassan, Panigrahi Rashmi, Lopez-Campistrous Ana, McMullen Todd, Reyes Ken, Anderson Elena, Krishnan Vidhya, Hernandez-Anzaldo Samuel, Zheng Xi-Long, Glover J N Mark, Hardy Eugenio, Fernandez-Patron Carlos
Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Nat Commun. 2025 Apr 22;16(1):3752. doi: 10.1038/s41467-025-59062-0.
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.
载脂蛋白A1（APOA1）在肝脏和肠道中合成，它在高密度脂蛋白中运输胆固醇，将其从动脉粥样硬化病变部位转运至肝脏，从而预防动脉粥样硬化斑块破裂。在此，我们发现，在人类和表达APOA1的小鼠体内，前MMP2（基质金属蛋白酶-2的酶原）与APOA1结合循环。这一点值得关注，因为MMP2是血液中含量最丰富的基质金属蛋白酶，且基质金属蛋白酶会促进动脉粥样硬化斑块破裂。基于人工智能（AlphaFold）的模型表明APOA1与MMP2相互作用；使用五种正交相互作用测定法证实了二者的直接相互作用，结果显示APOA1与MMP2的催化结构域和类血红素结合蛋白结构域结合。APOA1抑制MMP2自溶，并通过变构增加MMP2活性——人类和表达APOA1的小鼠血浆能特异性重现这种效应，但白蛋白以及APOA1基因敲除小鼠的血浆则不能。这些与APOA1的功能改变相互作用可能会增加MMP2的生物利用度，并为未来关于载脂蛋白和基质金属蛋白酶如何独立于胆固醇转运影响动脉粥样硬化斑块破裂的研究奠定基础。
