TY - JOUR
T1 - Synergistic roles of platelet-derived growth factor-BB and interleukin-1β in phenotypic modulation of human aortic smooth muscle cells
AU - Chen, Cheng Nan
AU - Li, Yi Shuan J.
AU - Yeh, Yi Ting
AU - Lee, Pei Ling
AU - Usami, Shunichi
AU - Chien, Shu
AU - Chiu, Jeng Jiann
PY - 2006/2/21
Y1 - 2006/2/21
N2 - The phenotype of smooth muscle cells (SMCs) plays an important role in vascular function in health and disease. We investigated the mechanism of modulation of SMC phenotype (from contractile to synthetic) induced by the synergistic action of a growth factor (platelet-derived growth factor, PDGF-BB) and a cytokine (interleukin, IL-1β). Human aortic SMCs grown on polymerized collagen showed high expression levels of contractile markers (smooth muscle α-actin, myosin heavy chain, and calponin). These levels were not significantly affected by PDGF-BB and IL-1β individually, but decreased markedly after the combined usage of PDGF-BB and IL-1β. PDGF/IL-1β costimulation also induced a sustained phosphorylation of Akt and p70 ribosomal 56 kinase (p70S6K). The effects of PDGF/IL-1β costimulation on contractile marker expression and Akt and p70S6K phosphorylation were blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 and by adenovirus expressing a dominant-negative Akt, and they were mimicked by constitutively active Akt. PDGF-BB/ IL-1β induced a sustained phosphorylation of PDGF receptor (PDGFR)-β and its association with IL-1 receptor (IL-1R1). Such activation and association of receptors were blocked by a PDGFR-β neutralizing antibody (AF385), an IL-1R1 antagonist (IL-1ra), as well as a specific inhibitor of PDGFR-β phosphorylation (AG1295); these agents also eliminated the PDGF-BB/IL-1β-induced signaling and phenotypic modulation. PDGF-BB/IL-1β inhibited the polymerized collagen-induced serum response factor DNA binding activity in the nucleus, and this effect was mediated by the PDGFR-β/IL-1R1 association and phosphatidylinositol 3-kinase Akt p70S6K pathway. Our findings provide insights into the mechanism of SMC phenotypic modulation from contractile to synthetic, e.g., in atherosclerosis.
AB - The phenotype of smooth muscle cells (SMCs) plays an important role in vascular function in health and disease. We investigated the mechanism of modulation of SMC phenotype (from contractile to synthetic) induced by the synergistic action of a growth factor (platelet-derived growth factor, PDGF-BB) and a cytokine (interleukin, IL-1β). Human aortic SMCs grown on polymerized collagen showed high expression levels of contractile markers (smooth muscle α-actin, myosin heavy chain, and calponin). These levels were not significantly affected by PDGF-BB and IL-1β individually, but decreased markedly after the combined usage of PDGF-BB and IL-1β. PDGF/IL-1β costimulation also induced a sustained phosphorylation of Akt and p70 ribosomal 56 kinase (p70S6K). The effects of PDGF/IL-1β costimulation on contractile marker expression and Akt and p70S6K phosphorylation were blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 and by adenovirus expressing a dominant-negative Akt, and they were mimicked by constitutively active Akt. PDGF-BB/ IL-1β induced a sustained phosphorylation of PDGF receptor (PDGFR)-β and its association with IL-1 receptor (IL-1R1). Such activation and association of receptors were blocked by a PDGFR-β neutralizing antibody (AF385), an IL-1R1 antagonist (IL-1ra), as well as a specific inhibitor of PDGFR-β phosphorylation (AG1295); these agents also eliminated the PDGF-BB/IL-1β-induced signaling and phenotypic modulation. PDGF-BB/IL-1β inhibited the polymerized collagen-induced serum response factor DNA binding activity in the nucleus, and this effect was mediated by the PDGFR-β/IL-1R1 association and phosphatidylinositol 3-kinase Akt p70S6K pathway. Our findings provide insights into the mechanism of SMC phenotypic modulation from contractile to synthetic, e.g., in atherosclerosis.
KW - Akt
KW - mTOR
KW - Signal transduction
KW - Smooth muscle phenotype
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U2 - 10.1073/pnas.0510973103
DO - 10.1073/pnas.0510973103
M3 - Article
C2 - 16477012
AN - SCOPUS:33644504832
VL - 103
SP - 2665
EP - 2670
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 8
ER -