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.
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
K
K
Yamamoto
Q N
QN
Dang
S P
SP
Kennedy
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R
Osathanondh
R A
RA
Kelly
R T
RT
Lee
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