Signaling mechanisms underlying strain-dependent brain natriuretic peptidegene transcription

Activation of brain natriuretic peptide (BNP) gene promoter activity repres ents one of the earliest and most reliable markers of ventricular cardiac m yocyte hypertrophy. We recently demonstrated that mechanical strain increas es immunoreactive BNP secretion, steady-state BNP mRNA levels and BNP gene transcriptional activity in neonatal rat myocyte cultures. We have also sho wn that strain-dependent BNP gene transcription is critically dependent on the functional integrity of a number of integrins (specfically beta1, beta3 , and alphav beta5 integrins) present on the surface of cardiac myocytes. W hen used alone, each of these antibodies resulted in a significant reductio n in strain-dependent activation of a transfected hBNP-luciferase reporter and inhibition of a number of signaling pathways that have been linked to s timulation of this reporter (e.g., extracellular signal regulated kinase an d c-Jun amino terminal kinase). The present study shows that combinations o f these antibodies resulted in further reductions in hBNP gene promoter act ivity and inhibition of the relevant signaling cascades. These studies prov ide further support for the importance of integrin-matrix interactions in p romoting strain-dependent changes in cardiac myocyte gene transcription.