TY - JOUR
T1 - Differential regulation of pregnancy associated plasma protein-A in human coronary artery endothelial cells and smooth muscle cells
AU - Conover, Cheryl A.
AU - Harrington, Sean C.
AU - Bale, Laurie K.
N1 - Funding Information:
The authors thank Nathan McMaster for his important contributions to this study. This work was supported in part by NIH Grant HL074871 to CAC.
PY - 2008/6
Y1 - 2008/6
N2 - 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)-α and interleukin (IL)-β, stimulated PAPP-A expression (TNF-α ≫ IL-1β), whereas there was no effect of IL-6, transforming growth factor-β, IGF-I, insulin, fibroblast growth factor or epidermal growth factor in these cells. Stimulation of PAPP-A expression by TNF-α was associated with significantly increased VCAM, ICAM, and MCP-1 expression but without major changes in other IGF system components. TNF-α-induced VCAM, ICAM, and MCP-1 expression (≤4 h) preceded PAPP-A expression (24 h). The anti-oxidant, N-acetyl cysteine, inhibited TNF-α-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-α. 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.
AB - 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)-α and interleukin (IL)-β, stimulated PAPP-A expression (TNF-α ≫ IL-1β), whereas there was no effect of IL-6, transforming growth factor-β, IGF-I, insulin, fibroblast growth factor or epidermal growth factor in these cells. Stimulation of PAPP-A expression by TNF-α was associated with significantly increased VCAM, ICAM, and MCP-1 expression but without major changes in other IGF system components. TNF-α-induced VCAM, ICAM, and MCP-1 expression (≤4 h) preceded PAPP-A expression (24 h). The anti-oxidant, N-acetyl cysteine, inhibited TNF-α-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-α. 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.
KW - Endothelial cells
KW - Insulin-like growth factor
KW - Interleukin-1β
KW - Low density lipoprotein
KW - Pregnancy-associated plasma protein-A
KW - Tumor necrosis factor-α
KW - Vascular cell adhesion molecule
UR - http://www.scopus.com/inward/record.url?scp=41649102627&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41649102627&partnerID=8YFLogxK
U2 - 10.1016/j.ghir.2007.09.001
DO - 10.1016/j.ghir.2007.09.001
M3 - Article
C2 - 17936662
AN - SCOPUS:41649102627
VL - 18
SP - 213
EP - 220
JO - Growth Hormone and IGF Research
JF - Growth Hormone and IGF Research
SN - 1096-6374
IS - 3
ER -