Synergistic roles of platelet-derived growth factor-BB and interleukin-1beta in phenotypic modulation of human aortic smooth muscle cells.
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-1beta). Human aortic SMCs grown on polymerized collagen showed high expression levels of contractile markers (smooth muscle alpha-actin, myosin heavy chain, and calponin). These levels were not significantly affected by PDGF-BB and IL-1beta individually, but decreased markedly after the combined usage of PDGF-BB and IL-1beta. PDGF/IL-1beta costimulation also induced a sustained phosphorylation of Akt and p70 ribosomal S6 kinase (p70S6K). The effects of PDGF/IL-1beta 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-1beta induced a sustained phosphorylation of PDGF receptor (PDGFR)-beta and its association with IL-1 receptor (IL-1R1). Such activation and association of receptors were blocked by a PDGFR-beta neutralizing antibody (AF385), an IL-1R1 antagonist (IL-1ra), as well as a specific inhibitor of PDGFR-beta phosphorylation (AG1295); these agents also eliminated the PDGF-BB/IL-1beta-induced signaling and phenotypic modulation. PDGF-BB/IL-1beta inhibited the polymerized collagen-induced serum response factor DNA binding activity in the nucleus, and this effect was mediated by the PDGFR-beta/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.
Chen
Cheng-Nan
CN
Division of Medical Engineering Research, National Health Research Institutes (Zhunan Campus), Miaoli 350, Taiwan, Republic of China.
Li
Yi-Shuan J
YS
Yeh
Yi-Ting
YT
Lee
Pei-Ling
PL
Usami
Shunichi
S
Chien
Shu
S
Chiu
Jeng-Jiann
JJ
D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D001018:Aortic Diseases / Q000201:enzymology; D050197:Atherosclerosis / Q000201:enzymology; D000077214:Becaplermin; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism
D000077214:Becaplermin; D003094:Collagen; D007375:Interleukin-1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D026362:Serum Response Factor