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.

Epithelial lining fluid free IGF-I-to-PAPP-A ratio is associated with bronchopulmonary dysplasia in preterm infants

“…The data reported in this study are in agreement with the idea that free IGF-I is increased at lung levels (ELF values) in affected infants, further confirmed by decreased PAPP-A levels, which are always inversely correlated in the different models studied (1,10). It has already been reported that tumor necrosis factor-␣ is able to reduce IGF-I and induce the release of PAPP-A molecules (1,10).…”

“…The latter is a 200-kDa metalloproteinase capable of inducing the dissociation of free IGF-I from three of the binding proteins (IGFBP-2, -4, and -5). In addition to the placenta, PAPP-A is expressed in a wide variety of reproductive and nonreproductive organs and fetal tissues, and many cells are able to produce PAPP-A, such as fibroblasts, endothelial cells, and smooth muscle cells (3,10,16,25).…”

Genetic Deletion of Pregnancy-Associated Plasma Protein-A Is Associated With Resistance to Atherosclerotic Lesion Development in Apolipoprotein E–Deficient Mice Challenged With a High-Fat Diet

“…28 TNF-␣ and IL-1␤ are potent stimulators of PAPP-A gene expression in coronary artery smooth muscle cells. 29 Thus, we speculate that upregulation of PAPP-A in vascular cells by macrophage-derived cytokines is an important component of lesion development, and, in the absence of this target gene, lesion development is blunted in spite of the continued presence of macrophages and similar levels of TNF-␣ and IL-1␤ expression in aortas from KO/KO and ApoE KO mice. Indeed, the percentage of lesion staining for macrophages was higher in KO/KO compared with ApoE KO mice, whereas the absolute area of macrophage staining was approximately the same in the 2 groups.…”

Pregnancy-associated plasma protein A: spotlight on kidney diseases

“…PAPP-A expression is stimulated by TNF-α and interleukin 1 beta (IL1-β ) (52 -54) and this cytokine induced expression can be inhibited by antioxidants N-acetyl cysteine (53) or polyphenol resveratrol (54) . Resveratrol is found in the skin of grapes and in red wine which might contribute to the explanation of the French paradox of benefi cial effect of consumption of red wine on reduced cardiovascular risk.…”