Surface association of pregnancy-associated plasma protein-A accounts for its colocalization with activated macrophages

Cheryl A. Conover, Sean C. Harrington, Laurie K. Bale, Claus Oxvig

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Intense immunostaining for pregnancy-associated plasma protein-A (PAPP-A), a newly characterized metalloproteinase in the insulin-like growth factor system, colocalizes with activated macrophages in human atherosclerotic plaque. To determine macrophage regulation of PAPP-A expression, we developed two models of human macrophages with basal and activated phenotypes. THP-1 cells and peripheral blood monocytes could be differentiated into macrophages and activated upon specific treatment regimens with phorbol myristate acetate, macrophage colony-stimulating factor, and interleukin-1β. Activation was assessed by cell secretion of tumor necrosis factor-α, which increased 30- to 100-fold with activation. Activated macrophages also secreted matrix metalloproteinase-9. However, no PAPP-A mRNA or PAPP-A antigen could be detected in these cells under any condition. Upon incubation with recombinant PAPP-A, we found that activated macrophages bound and internalized more PAPP-A than unactivated macrophages or monocytes. Internalization accounted for at least 50% of macrophage-associated PAPP-A, as assessed in studies with cytochalasin B. Membrane-bound PAPP-A retained protease activity, whereas internalized PAPP-A had little or no activity. Similar experiments carried out with a mutated variant of PAPP-A, which retains functionality as a protease but is unable to bind surface-associated glycosaminoglycan, showed no macrophage association or internalization. Absence of PAPP-A expression was confirmed in activated macrophages isolated from a hypercholesterolemic rabbit model of atherosclerosis. We therefore conclude that PAPP-A is not synthesized in, but rather is bound and internalized by, macrophages. Our findings likely account for the observed intense immunostaining for PAPP-A colocalizing with activated macrophages and may have physiological significance in the development of vulnerable plaque.

Original languageEnglish (US)
Pages (from-to)H994-H1000
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume292
Issue number2
DOIs
StatePublished - Feb 1 2007

Keywords

  • Atherosclerotic plaque
  • Macrophages

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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