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Background

Pregnancy-associated plasma protein-A (PAPP-A), a metalloproteinase that serves to modulate local insulin-like growth factor (IGF) action, is upregulated in atherosclerotic plaque. However, little is known about the cellular mechanisms underlying this elevated PAPP-A.

Objective

To continue study of PAPP-A expression and its regulation in human vascular cells, with a focus on endothelial cells.

Design

Primary cultures of human coronary artery endothelial cells (ECs) were treated without and with cytokines, growth factors, or low density lipoprotein (LDL). PAPP-A mRNA, protein, and protease activity were assessed using real-time PCR, ultra-sensitive PAPP-A ELISA and cell-free proteolysis of IGF binding protein (IGFBP-4), respectively. In addition, vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), monocyte chemotactic protein (MCP-1), IGF-I, IGF-I receptor, and IGFBP-4 and -5 mRNA expression levels were determined.

Results

ECs in culture show little basal PAPP-A expression. The pro-inflammatory cytokines, tumor necrosis factor (TNF)-alpha and interleukin (IL)-beta, stimulated PAPP-A expression (TNF-alpha>>IL-1beta), whereas there was no effect of IL-6, transforming growth factor-beta, IGF-I, insulin, fibroblast growth factor or epidermal growth factor in these cells. Stimulation of PAPP-A expression by TNF-alpha was associated with significantly increased VCAM, ICAM, and MCP-1 expression but without major changes in other IGF system components. TNF-alpha-induced VCAM, ICAM, and MCP-1 expression (4h) preceded PAPP-A expression (24h). The anti-oxidant, N-acetyl cysteine, inhibited TNF-alpha-induced PAPP-A expression without altering the induction in VCAM, ICAM, and MCP-1. Treatment with native or oxidized LDL had no effect on PAPP-A expression in ECs. Comparative results in human coronary smooth muscle cells indicated qualitative and quantitative differences in PAPP-A expression and regulation between the two vascular cell types.

Conclusions

Human coronary artery ECs express PAPP-A mRNA and functional protein when activated by the pro-inflammatory cytokine, TNF-alpha. This study complements work on PAPP-A expression in human coronary artery SMCs and human monocyte-derived macrophages and suggests an interactive model of PAPP-A regulation and action in human atherosclerotic plaque."xsd:string
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http://purl.uniprot.org/citations/17936662http://purl.uniprot.org/core/author"Conover C.A."xsd:string
http://purl.uniprot.org/citations/17936662http://purl.uniprot.org/core/author"Bale L.K."xsd:string
http://purl.uniprot.org/citations/17936662http://purl.uniprot.org/core/author"Harrington S.C."xsd:string
http://purl.uniprot.org/citations/17936662http://purl.uniprot.org/core/date"2008"xsd:gYear
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http://purl.uniprot.org/citations/17936662http://purl.uniprot.org/core/pages"213-220"xsd:string
http://purl.uniprot.org/citations/17936662http://purl.uniprot.org/core/title"Differential regulation of pregnancy associated plasma protein-A in human coronary artery endothelial cells and smooth muscle cells."xsd:string
http://purl.uniprot.org/citations/17936662http://purl.uniprot.org/core/volume"18"xsd:string
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