Synergistic roles of platelet-derived growth factor-BB and interleukin-1β in phenotypic modulation of human aortic smooth muscle cells

Abstract

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-1␤). Human aortic SMCs grown on polymerized collagen showed high expression levels of contractile markers (smooth muscle ␣-actin, myosin heavy chain, and calponin). These levels were not significantly affected by PDGF-BB and IL-1␤ individually, but decreased markedly after the combined usage of PDGF-BB and IL-1␤. PDGF͞IL-1␤ costimulation also induced a sustained phosphorylation of Akt and p70 ribosomal S6 kinase (p70S6K). The effects of PDGF͞IL-1␤ 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. -1ra), as well as a specific inhibitor of PDGFR-␤ phosphorylation (AG1295); these agents also eliminated the PDGF-BB͞IL-1␤-induced signaling and phenotypic modulation. PDGF-BB͞IL-1␤ inhibited the polymerized collagen-induced serum response factor DNA binding activity in the nucleus, and this effect was mediated by the PDGFR-␤͞IL-1R1 association and phosphatidylinositol 3-kinase͞Akt͞p70S6K pathway. Our findings provide insights into the mechanism of SMC phenotypic modulation from contractile to synthetic, e.g., in atherosclerosis. PDGF-BB͞ IL-1␤ induced a sustained phosphorylation of PDGF receptor (PDGFR)-␤ and its association with IL-1 receptor (IL-1R1). Such activation and association of receptors were blocked by a PDGFR-␤ neutralizing antibody (AF385), an IL-1R1 antagonist (ILsignal transduction ͉ smooth muscle phenotype ͉ Akt ͉ mTOR

Nifedipine Inhibits Vascular Smooth Muscle Cell Dedifferentiation via Downregulation of Akt Signaling

“…Recently, costimulation with PDGF-BB and interleukin 1␤ has been proved to induce sustained activation of Akt and p70S6K. 22 In the present study, we showed that nifedipine suppresses PDGF-induced increases in phospho-Akt expression. Our preliminary experiments also showed that nifedipine inhibits increases in both phosho-Akt1 and phospho-Akt2 (data not shown).…”

Differential Behaviors of Atrial Versus Ventricular Fibroblasts

“…PDGF, a regulatory peptide stimulated by tissue injury, activates PDGFR tyrosine kinase, initiating multiple secondary messenger signaling cascades, 15,40 and synergizes with other growth factors, in particular TGF␤ 1 , in an autocrine and a paracrine fashion. 16,41,42 TGF␤ 1 -induced proliferation in some systems requires the induction of PDGF in the presence of unmethylated PDGF DNA. 42 Cardiac-restricted overexpression of either PDGF-C or PDGF-D isoforms cause fibrosis and dilated cardiomyopathy.…”

Regulation of vascular smooth muscle cell phenotype.

“…A p value <0.05 was considered significant. These results confirm previous findings [36,50,162] showing that PDGF promotes phenotypic transition of VSMCs.…”

“…For example, it was shown that PDGF and IL 1-13 can act synergistically to promote the development of the synthetic phenotype [50]. Extracellular matrix proteins such as polymerized collagen have been shown to cause down regulation of genes such as thrombospondin and fibronectin, which are known to be upregulated in injured vessels [51].…”

“…Activation of the Erk1/2 and Akt pathways is known to play important roles in PDGF-induced VSMC proliferation, migration and phenotype switching [50]. The activation of the other MAPKs by PDGF also has profound effects on SMC behavior.…”