Abstract
We have previously found that overexpression of CHF1/Hey2 in the myocardium prevents the development of phenylephrine-induced hypertrophy. To identify transcriptional pathways regulated by CHF1/Hey2, we cultured primary neonatal mouse cardiac myocytes from wild type and transgenic mice overexpressing CHF1/Hey2 and treated them with serum, a potent hypertrophic stimulus. We verified that overexpression of CHF1/Hey2 suppressed cardiac myocyte hypertrophy induced by serum and then determined transcriptional profiles by microarray hybridization. We identified and verified important downstream target genes by single gene analysis and qRT-PCR and then identified important biological processes by Gene Set Analysis using Biological Process Gene Sets from the Gene Ontology Consortium. We found that CHF1/Hey2 suppresses pathways involved in water transport, adenylate cyclase activity, embryonic eye morphogenesis, gut development and fluid transport after serum stimulation. Genes involved in protein dephosphorylation, demonstrate increased expression in myocytes overexpressing CHF1/Hey2, independent of serum treatment. Genes overexpressed prior to serum treatment are involved in regulation of transcription factor activity, nuclear protein export and steroid hormone receptor signaling. Genes overexpressed after serum treatment are involved in autophagy, apoptosis and mitochondrial biogenesis.
Highlights
Cardiac hypertrophy is an important biological process in which individual cardiac myocytes enlarge in response to exogenous stimuli
In order to identify pathways relevant to cardiac hypertrophy in the cardiac myocyte transcriptome that are regulated by CHF1/Hey2, we examined the expression of genes in isolated wild type and transgenic myocytes treated with serum, a potent hypertrophic stimulus
We have previously reported that CHF1/Hey2 can attenuate the hypertrophic response of cardiac myocytes to phenylephrine in vivo and in vitro [1]
Summary
Cardiac hypertrophy is an important biological process in which individual cardiac myocytes enlarge in response to exogenous stimuli. Hypertrophy is initially compensatory, prolonged exposure to hypertrophic stimuli can lead to contractile dysfunction and apoptotic cell death, resulting in cardiac failure and fibrosis. Understanding the molecular basis for the development of hypertrophy, its progression to heart failure and the biological pathways involved in this syndrome will have important preventative, diagnostic and therapeutic implications. We have previously reported that the Hairy-related bHLH transcriptional repressor, CHF1 ( called Hey, Hesr-2, Hrt, HERP1 and gridlock), functions as a suppressor of cardiac hypertrophy induced by phenylephrine [1]. Suppression of cardiac hypertrophy is mediated, at least in part, by the binding of CHF1/Hey to the transcription factor
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