title: SRF-dependent gene expression in isolated cardiomyocytes: regulation of genes involved in cardiac hypertrophy.
abstract: Serum response factor (SRF) is a transcription factor required for the regulation of genes important for cardiac structure and function. Notably, the "fetal gene expression profile" that is characteristic of cardiac hypertrophy consists of genes known to be regulated by SRF. Transgenic animal studies suggest that cardiac-specific overexpression of SRF induces this pattern of hypertrophic genes and subsequently causes the progression of pathologic adaptations. Furthermore, studies examining cardiac tissues from patients with severe heart failure indicate significant alterations in SRF expression that correspond with alterations in expression of SRF-dependent genes. Based on these observations, it has been postulated that SRF may be critical for stimulating pathologic gene expression at the onset of hypertrophic adaptation. To address the role of SRF in cardiac hypertrophy we investigated whether SRF is necessary and sufficient for the expression of genes associated with the hypertrophic response. We used isolated cardiomyocytes from both neonatal rats, and transgenic mice containing floxed SRF alleles, to examine cardiac gene expression in response to overexpression and absence of SRF. Using this approach, we demonstrate that SRF is required for the induction of atrial naturetic factor (ANF), c-fos, NCX1, BNP, alpha-actins, alpha-myosin heavy chain, and beta-myosin heavy chain genes. However, overexpression of exogenous SRF in isolated cardiomyocytes is only sufficient to induce NCX1 and alpha-myosin heavy chain. These results indicate that SRF is critical for the regulation and induction of genes associated with the progression of pathologic cardiac hypertrophy, however, the pattern of genes induced by overexpression of SRF in isolated cardiomyocytes is different from those genes expressed in hypertrophic transgenic hearts. This suggests that SRF-dependent gene expression is modulated in a complex manner by in vivo physiologic systems prior to and during heart failure as the organism adapts to cardiac stress.
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, 53226, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Nelson
authors.forename: Robert
authors.initials: R
authors.lastname: Balza
authors.forename: Qi
authors.initials: Q
authors.lastname: Xiao
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Misra
mesh_terms: D000199:Actins / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D019084:Fluorescent Antibody Technique, Indirect; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D008156:Luciferases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026362:Serum Response Factor / Q000235:genetics* / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000235:genetics
chemical_list: D000199:Actins; D016760:Proto-Oncogene Proteins c-fos; D026362:Serum Response Factor; D019831:Sodium-Calcium Exchanger; D020097:Natriuretic Peptide, Brain; D049452:Green Fluorescent Proteins; D009320:Atrial Natriuretic Factor; D008156:Luciferases; D018995:Myosin Heavy Chains