Signaling mechanisms underlying strain-dependent brain natriuretic peptide gene transcription.
Activation of brain natriuretic peptide (BNP) gene promoter activity represents one of the earliest and most reliable markers of ventricular cardiac myocyte hypertrophy. We recently demonstrated that mechanical strain increases immunoreactive BNP secretion, steady-state BNP mRNA levels and BNP gene transcriptional activity in neonatal rat myocyte cultures. We have also shown that strain-dependent BNP gene transcription is critically dependent on the functional integrity of a number of integrins (specfically beta1, beta3, and alpha(v)beta5 integrins) present on the surface of cardiac myocytes. When used alone, each of these antibodies resulted in a significant reduction in strain-dependent activation of a transfected hBNP-luciferase reporter and inhibition of a number of signaling pathways that have been linked to stimulation of this reporter (e.g., extracellular signal regulated kinase and c-Jun amino terminal kinase). The present study shows that combinations of these antibodies resulted in further reductions in hBNP gene promoter activity and inhibition of the relevant signaling cascades. These studies provide further support for the importance of integrin-matrix interactions in promoting strain-dependent changes in cardiac myocyte gene transcription.
Liang
F
F
Department of Medicine, University of California, San Francisco 94143-0540, USA.
Kovacic-Milivojevic
B
B
Chen
S
S
Cui
J
J
Roediger
F
F
Intengan
H
H
Gardner
D G
DG
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D016023:Integrins / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis* / Q000235:genetics; D010957:Plasmids; D011233:Precipitin Tests; D051381:Rats; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013314:Stress, Mechanical; D014158:Transcription, Genetic / Q000235:genetics*; D014162:Transfection; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases
D002352:Carrier Proteins; D016023:Integrins; D016328:NF-kappa B; D020097:Natriuretic Peptide, Brain; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D001616:beta-Galactosidase