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: Cheryl A Conover, Laurie K Bale, Claus Oxvig
• Journal: Journal of cardiovascular translational research (J Cardiovasc Transl Res) Vol. 9 Issue 1 Pg. 77-9 (Feb 2016) ISSN: 1937-5395 [Electronic] United States
• PMID: 26733326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Apolipoproteins E
• Protease Inhibitors
• Triglycerides
• Cholesterol
• Pregnancy-Associated Plasma Protein-A

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Aorta (drug effects, enzymology, immunology, pathology)
• Aortic Diseases (enzymology, genetics, immunology, prevention & control)
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (enzymology, genetics, immunology, prevention & control)
• Cholesterol (blood)
• Diet, High-Fat
• Disease Models, Animal
• Feasibility Studies
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Targeted Therapy
• Plaque, Atherosclerotic
• Pregnancy-Associated Plasma Protein-A (antagonists & inhibitors, immunology, metabolism)
• Protease Inhibitors (pharmacology)
• Time Factors
• Triglycerides (blood)