Abstract
In addition to their role in cytokine gene regulation in T cells, nuclear factors of activated T cells (NFATs) have been shown to be involved in cardiac development and hypertrophy. We have reported previously that NFATs play an important role in the regulation of vascular smooth muscle cell (VSMC) proliferation by receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR) agonists, platelet-derived growth factor-BB (PDGF-BB) and thrombin, respectively. To understand the role of NFATs in vascular disease and development, we have now studied the role of these transcriptional factors in VSMC motility. PDGF-BB and thrombin induced VSMC motility in a dose-dependent manner. Blockade of NFAT activation resulted in substantial reduction in PDGF-BB- and thrombin-induced VSMC motility. PDGF-BB and thrombin also induced interleukin-6 (IL-6) expression in NFAT-dependent manner. Furthermore, IL-6 dose-dependently caused VSMC motility. A neutralizing anti-rat IL-6 antibody inhibited VSMC motility induced by IL-6, PDGF-BB, and thrombin. In addition, exogenous addition of IL-6 rescued both PDGF-BB- and thrombin-induced VSMC motility from inhibition by the blockade of NFAT activation. Together, these results for the first time demonstrate that NFATs mediate both RTK and GPCR agonist-induced VSMC motility via induction of expression of IL-6.
Highlights
vascular smooth muscle cell (VSMC) acquire their embryonic non-contractile and synthetic state phenotype and via their migration from media to intima and multiplication in intima contribute to the progression of lesions such as restenosis after angioplasty [10]
We have reported previously that nuclear factors of activated T cells (NFATs) play an important role in the regulation of vascular smooth muscle cell (VSMC) proliferation by receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR) agonists, platelet-derived growth factor-BB (PDGF-BB) and thrombin, respectively
We have reported that the RTK and GPCR agonists, PDGF-BB and thrombin, respectively, cause translocation of NFATs, NFATc1, from the cytoplasm to the nucleus in VSMC [29]
Summary
VSMC acquire their embryonic non-contractile and synthetic state phenotype and via their migration from media to intima and multiplication in intima contribute to the progression of lesions such as restenosis after angioplasty [10]. Toward understanding the functional role of NFATs in non-immune cells, we have reported previously that their activation is required for RTK and GPCR agonist-induced VSMC proliferation [29].
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