Abstract
Ets-1 is a transcription factor that activates expression of matrix-degrading proteinases such as collagenase and stromelysin. To study the control of ets-1 gene expression in rat vascular smooth muscle cells (VSMC), cells were exposed to factors known to regulate VSMC migration and proliferation. Platelet-derived growth factor-BB (PDGF-BB), endothelin-1 (ET-1), and phorbol 12-myristate 13-acetate (PMA) induced a dose-dependent expression of ets-1 mRNA. These effects were abrogated by inhibition of protein kinase C (PKC) by H-7 or chronic PMA treatment. Ets-1 mRNA was superinduced by PDGF-BB and ET-1 in the presence of cycloheximide. The chelation of intracellular Ca2+ by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester and the depletion of endoplasmic reticulum intracellular Ca2+ concentration ([Ca2+]i) by thapsigargin inhibited PDGF-BB- and ET-1-induced ets-1 mRNA, whereas ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid had no effect. However, [Ca2+]i release alone was not sufficient to increase ets-1 mRNA. Forskolin blocked ET-1-, PDGF-BB-, and PMA-induced ets-1 mRNA, as well as inositol phosphate formation, consistent with an effect through impairment of PKC activation. Inhibitors of ets-1 gene expression, such as H-7 and herbimycin A, inhibited the ET-1 induction of collagenase I mRNA. We propose that ets-1 may be an important element in the orchestration of matrix proteinase expression and of vascular remodeling after arterial injury.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
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Animals
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Becaplermin
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Benzoquinones
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Calcium / metabolism
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Cells, Cultured
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Collagenases / genetics
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Collagenases / metabolism
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Culture Media, Serum-Free
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Cyclic AMP / pharmacology
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Cycloheximide / pharmacology
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Endoplasmic Reticulum / metabolism
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Endothelin-1 / pharmacology*
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Extracellular Matrix / metabolism
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Gene Expression Regulation / drug effects*
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Lactams, Macrocyclic
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / metabolism*
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Platelet-Derived Growth Factor / pharmacology*
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Protein Kinase C / metabolism
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Protein Synthesis Inhibitors / pharmacology
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins c-ets
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Proto-Oncogene Proteins c-sis
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Quinones / pharmacology
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Rifabutin / analogs & derivatives
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Transcription Factors / genetics*
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Transcription, Genetic / drug effects
Substances
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Benzoquinones
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Culture Media, Serum-Free
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Endothelin-1
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Enzyme Inhibitors
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Ets1 protein, rat
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Lactams, Macrocyclic
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Platelet-Derived Growth Factor
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Protein Synthesis Inhibitors
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-ets
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Proto-Oncogene Proteins c-sis
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Quinones
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RNA, Messenger
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Transcription Factors
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Becaplermin
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Rifabutin
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herbimycin
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Cycloheximide
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Cyclic AMP
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Protein Kinase C
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Collagenases
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Calcium