Abstract
The metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A), has been implicated in the development of cardiovascular disease in humans and mouse models. In the latter, genetic deletion or overexpression of PAPP-A confirmed a major role for PAPP-A in atherosclerosis. In this study, we tested the hypothesis that targeting PAPP-A proteolytic activity by an inhibitory monoclonal antibody (mAb-PA) reduces atherosclerotic plaque progression. Apolipoprotein E knock-out mice on high-fat diet were treated with mAb-PA or isotype control. Control mice had a 10-fold increase in aortic plaque after 10 weeks. Aortic plaque burden was reduced by ∼70 % in mice treated with mAb-PA (P = 0.0002). Treatment was efficacious even in the face of elevated cholesterol and triglycerides. This study demonstrates proof-of-principle and provides feasibility for a novel therapeutic strategy to inhibit atherosclerotic plaque burden by selective targeting of PAPP-A.
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References
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Funding
This work was supported by a grant from the Ted Nash Long Life Foundation (to C.A.C.) and by grants from the Novo Nortic Foundation and the Danish Heart Association (to C.O.).
Conflict of Interest
C.A.C. and C.O. are inventors on patent application (US 7115382) relating to the use of pregnancy-associated plasma protein-A
Ethical Approval (Animals)
All procedures involving mice complied with the standards set in the Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of Mayo Clinic (A56213).
Ethical Approval (Humans)
This article does not contain any studies with human participants performed by any of the authors.
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Editor-in-Chief Jennifer L. Hall oversaw the review of this article
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Conover, C.A., Bale, L.K. & Oxvig, C. Targeted Inhibition of Pregnancy-Associated Plasma Protein-A Activity Reduces Atherosclerotic Plaque Burden in Mice. J. of Cardiovasc. Trans. Res. 9, 77–79 (2016). https://doi.org/10.1007/s12265-015-9666-9
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DOI: https://doi.org/10.1007/s12265-015-9666-9