Premium
Plasminogen activator inhibitor‐1 (PAI‐1) expression in vascular smooth muscle cells involves a SRC/MEK/USF signal cascade
Author(s) -
Higgins P. J.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.11.043
Subject(s) - kinase , mapk/erk pathway , activator (genetics) , biology , vascular smooth muscle , transcription factor , proto oncogene tyrosine protein kinase src , cancer research , signal transduction , transfection , microbiology and biotechnology , phosphorylation , plasminogen activator , mek inhibitor , plasminogen activator inhibitor 1 , gene , endocrinology , biochemistry , smooth muscle
Background High PAI‐1 levels associate with increased cardiovascular disease risk. PAI‐1 targeting may be an important approach to the therapy of vascular disorders. Methods Pathway‐specific pharmacologic/molecular agents were used to define signaling events associated with PAI‐1 expression. Results MEK (PD98059, U0126) or src family (PP1) kinase inhibitors attenuated growth factor‐stimulated PAI‐1 transcription in smooth muscle cells. PP1 blocked ERK1/2 activation suggesting that the required src kinase is upstream of ERK1/2. Transfection of a dominant‐negative pp60c‐src construct, moreover, reduced PAI‐1 levels to that of PP1‐treated controls implicating pp60c‐src as the involved src kinase. An E box motif in the PAI‐1 promoter was determined to be a USF‐1 binding site. Mutation of this site or transfection of dominant‐negative USF‐1 constructs attenuated PAI‐1 expression in smooth muscle cells. Nuclear USF‐1 was determined to be a phosphorylation target of translocated ERK1/2 by both in situ co‐localization microscopy and co‐immunoprecipitation. Conclusions A major phenotypic characteristic of “activated” smooth muscle cells (i.e., transcription of fibrosis‐associated target genes[e.g., PAI‐1]) requires pp60c‐src kinase activity and MEK signaling and involves activation of the USF transcription factor likely by ERK family MAP kinases. Pharmacologic or genetically‐targeted manipulation of this pathway may have therapeutic usefulness in treatment of vascular disease. Clinical Pharmacology & Therapeutics (2005) 77 , P11–P11; doi: 10.1016/j.clpt.2004.11.043