title: Targeted Inhibition of Pregnancy-Associated Plasma Protein-A Activity Reduces Atherosclerotic Plaque Burden in Mice.
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.
authors.affiliation: Division of Endocrinology, Endocrine Research Unit, Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, MN, 55905, USA. conover@mayo.edu.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Conover
authors.affiliation: Division of Endocrinology, Endocrine Research Unit, Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, MN, 55905, USA. Bale.Laurie@mayo.edu.
authors.forename: Laurie K
authors.initials: LK
authors.lastname: Bale
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. co@mbg.au.dk.
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005240:Feasibility Studies; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D058226:Plaque, Atherosclerotic; D011266:Pregnancy-Associated Plasma Protein-A / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D011480:Protease Inhibitors; D014280:Triglycerides; D002784:Cholesterol; D011266:Pregnancy-Associated Plasma Protein-A
keywords: Atherosclerosis; Insulin-like growth factor; Monoclonal antibody; Pregnancy-associated plasma protein-A