Abstract
Mechanical overload may change cardiac structure through angiotensin II-dependent and angiotensin II-independent mechanisms. We investigated the effects of mechanical strain on the gene expression of tenascin-C, a prominent extracellular molecule in actively remodeling tissues, in neonatal rat cardiac myocytes. Mechanical strain induced tenascin-C mRNA (3.9 +/- 0.5-fold, p < 0.01, n = 13) and tenascin-C protein in an amplitude-dependent manner but did not induce secreted protein acidic and rich in cysteine nor fibronectin. RNase protection assay demonstrated that mechanical strain induced all three alternatively spliced isoforms of tenascin-C. An angiotensin II receptor type 1 antagonist inhibited mechanical induction of brain natriuretic peptide but not tenascin-C. Antioxidants such as N-acetyl-L-cysteine, catalase, and 1, 2-dihydroxy-benzene-3,5-disulfonate significantly inhibited induction of tenascin-C. Truncated tenascin-C promoter-reporter assays using dominant negative mutants of IkappaBalpha and IkappaB kinase beta and electrophoretic mobility shift assays indicated that mechanical strain increases tenascin-C gene transcription by activating nuclear factor-kappaB through reactive oxygen species. Our findings demonstrate that mechanical strain induces tenascin-C in cardiac myocytes through a nuclear factor-kappaB-dependent and angiotensin II-independent mechanism. These data also suggest that reactive oxygen species may participate in mechanically induced left ventricular remodeling.
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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1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / pharmacology
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Acetylcysteine / pharmacology
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Alternative Splicing
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Angiotensin Receptor Antagonists
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Animals
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Animals, Newborn
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Antioxidants / pharmacology*
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Catalase / pharmacology
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Fibronectins / genetics
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Gene Expression Regulation* / drug effects
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Genes, Reporter
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Heart Ventricles
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I-kappa B Kinase
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I-kappa B Proteins*
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Indazoles / pharmacology
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Myocardium / cytology*
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Myocardium / metabolism*
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NF-KappaB Inhibitor alpha
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Osteonectin / genetics
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Promoter Regions, Genetic
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Protein Isoforms / genetics
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA, Messenger / genetics
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / metabolism*
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Receptor, Angiotensin, Type 1
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Receptor, Angiotensin, Type 2
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Stress, Mechanical
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Tenascin / biosynthesis
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Tenascin / genetics*
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Transcription, Genetic* / drug effects
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Transfection
Substances
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Angiotensin Receptor Antagonists
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Antioxidants
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DNA-Binding Proteins
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Fibronectins
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I-kappa B Proteins
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Indazoles
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Nfkbia protein, rat
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Osteonectin
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Protein Isoforms
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RNA, Messenger
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Reactive Oxygen Species
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Receptor, Angiotensin, Type 1
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Receptor, Angiotensin, Type 2
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Tenascin
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NF-KappaB Inhibitor alpha
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1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
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Catalase
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Protein Serine-Threonine Kinases
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I-kappa B Kinase
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7-nitroindazole
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Acetylcysteine