Induction of tenascin-C in cardiac myocytes by mechanical deformation. Role of reactive oxygen species.
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.
Yamamoto
K
K
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Dang
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Kennedy
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Osathanondh
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Kelly
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Lee
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D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D017398:Alternative Splicing; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006352:Heart Ventricles; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D007191:Indazoles / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D015676:Osteonectin / Q000235:genetics; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013314:Stress, Mechanical; D019063:Tenascin / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D057911:Angiotensin Receptor Antagonists; D000975:Antioxidants; D004268:DNA-Binding Proteins; D005353:Fibronectins; D020672:I-kappa B Proteins; D007191:Indazoles; C000606206:Nfkbia protein, rat; D015676:Osteonectin; D020033:Protein Isoforms; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D019063:Tenascin; D000072000:NF-KappaB Inhibitor alpha; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D002374:Catalase; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; C080122:7-nitroindazole; D000111:Acetylcysteine