title: Cytokine stimulation of pregnancy-associated plasma protein A expression in human coronary artery smooth muscle cells: inhibition by resveratrol.
abstract: Through specific cleavage of proteins that bind and inhibit insulin-like growth factor-I (IGF-I), pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF-I availability, and, consequently, receptor activation. PAPP-A expression is increased in experimental models of vascular injury and in human atherosclerotic plaque; however, little is known about the regulation of PAPP-A gene expression in vascular cells. In this study, we tested the hypothesis that proinflammatory cytokines involved in the vascular injury response stimulate PAPP-A gene expression in human coronary artery smooth muscle cells (hCASMC) in culture. Tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta stimulated PAPP-A gene expression in a time- and dose-dependent manner. The effect of these cytokines appears to be at the level of transcription because actinomycin D completely prevented the induction of PAPP-A gene expression. Accumulation of PAPP-A in cell-conditioned medium paralleled mRNA synthesis, as did proteolytic activity against IGF binding protein-4 (IGFBP-4). Interestingly, pretreatment of hCASMC with resveratrol, a polyphenol found in the skin of grapes and in red wine purported to underlie the "French paradox," inhibited TNF-alpha- and IL-1beta-induced PAPP-A expression and, hence, its IGFBP-4 proteolytic activity. Resveratrol had no effect on basal PAPP-A expression and protease activity. Our finding that PAPP-A gene expression in hCASMC is stimulated by TNF-alpha and IL-1beta suggests a mechanism for the regulation of PAPP-A in response to vascular injury that may contribute to the enhanced IGF-I bioactivity in intimal hyperplasia and atherosclerotic plaque development. Our results also suggest that PAPP-A may be a target of the cardiovascular system-protective effects of resveratrol.
authors.affiliation: Department of Internal Medicine, Endocrine Research Unit, Rochester, MN 55905, USA. Conover.Cheryl@mayo.edu
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Conover
authors.forename: Laurie K
authors.initials: LK
authors.lastname: Bale
authors.forename: Sean C
authors.initials: SC
authors.lastname: Harrington
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Resch
authors.forename: Michael T
authors.initials: MT
authors.lastname: Overgaard
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics* / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D027843:Vitis; D014920:Wine
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018974:Insulin-Like Growth Factor Binding Protein 4; D007375:Interleukin-1; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D011266:Pregnancy-Associated Plasma Protein-A; D000077185:Resveratrol