Angiotensin II type _1a receptor gene expression in the heart: AP-1 and GATA-4 participate in the response to pressure overload

Abstract

Hypertrophy of mammalian cardiac muscle is mediated, in part, by angiotensin II through an angiotensin II type 1a receptor (AT 1a R)-dependent mechanism. To understand how the level of AT 1a Rs is altered in this pathological state, we studied the expression of an injected AT 1a R promoter-luciferase reporter gene in adult rat hearts subjected to an acute pressure overload by aortic coarctation. This model was validated by demonstrating that coarctation increased expression of the ␣-skeletal actin promoter 1.7-fold whereas the ␣-myosin heavy chain promoter was unaffected. Pressure overload increased expression from the AT 1a R promoter by 1.6-fold compared with controls. Mutations introduced into consensus binding sites for AP-1 or GATA transcription factors abolished the pressure overload response but had no effect on AT 1a R promoter activity in control animals. In extracts from coarcted hearts, but not from control hearts, a Fos-JunB-JunD complex and GATA-4 were detected in association with the AP-1 and GATA sites, respectively. These results establish that the AT 1a R promoter is active in cardiac muscle and its expression is induced by pressure overload, and suggest that this response is mediated, in part, by a functional interaction between AP-1 and GATA-4 transcription factors.Pathological conditions resulting in increased cardiac workload generally are associated with activation of systemic and local renin-angiotensin systems and increased levels of circulating angiotensin II (AngII) (1, 2). However, little is understood about how AngII type 1a receptors (AT 1a R) are modulated under these same pathological conditions. AngII is a potent growth factor that mediates the hypertrophic growth of cardiac muscle cells and is a chemical mediator of stretchinduced cardiomyocyte hypertrophy (3-7). The interaction of AngII with AT 1a R activates a signal transduction cascade that effects the phosphorylation of serum response factor and p62 TCF by pp90 RSK and mitogen-activated protein kinase, respectively, resulting in increased c-fos gene expression (5-7). Hypertrophic stimuli also increase the level of AT1 a R mRNA in cardiomyocytes. A 3-fold increase in AT 1a R mRNA and a 2-fold increase in AT 1a R densities have been reported in spontaneously hypertensive and two kidney one-clip renovascular hypertensive rats with established cardiac hypertrophy (8). It is not known whether this increase in AT 1a R mRNA is mediated by a transcriptional or posttranscriptional mechanism.In this study, we use direct injection of DNA into the heart in conjunction with aortic coarctation (CoA) to study the activity of the AT 1a R promoter in the normal and pressureoverloaded rat heart. The AT 1a R promoter was found to be active in normal adult cardiac muscle, whereas gene expression was increased in response to an acute pressure overload (PO). The induced expression was blocked by mutation of either an AP-1 or a GATA binding site, however, these mutations had no effect on basal expression. Administration of the angiotensin-...

Distinct regulation of B-type natriuretic peptide transcription by p38 MAPK isoforms

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Identification of a chromosome 8p locus for early-onset coronary heart disease in a French Canadian population

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