Abstract
The early growth response transcription factor Egr-1 controls cell specific responses to proliferation, differentiation and apoptosis. Expression of Egr-1 and downstream transcription is closely controlled and cell specific upregulation induced by processes such as hypoxia and ischemia has been previously linked to multiple aspects of cardiovascular injury. In this study, we showed constitutive expression of Egr-1 in cultured human ventricular cardiac fibroblasts, used adenoviral mediated gene transfer to study the effects of continuous Egr-1 overexpression and studied downstream transcription by Western blotting, immunohistochemistry and siRNA transfection. Apoptosis was assessed by fluorescence microscopy and flow cytometry in the presence of caspase inhibitors. Overexpression of Egr-1 directly induced apoptosis associated with caspase activation in human cardiac fibroblast cultures in vitro assessed by fluorescence microscopy and flow cytometry. Apoptotic induction was associated with a caspase activation associated loss of mitochondrial membrane potential and transient downstream transcriptional up-regulation of the pro-apoptotic gene product Siva-1. Suppression of Siva-1 induction by siRNA partially reversed Egr-1 mediated loss of cell viability. These findings suggest a previously unknown role for Egr-1 and transcriptional regulation of Siva-1 in the control of cardiac accessory cell death.
Highlights
Cardiac fibroblasts are the predominant cell type in healthy heart tissue [1] secreting structural collagen, providing an extracellular matrix and supporting the function of contractile cardiomyocytes [2,3,4]
Infection of cardiac fibroblasts with AdEgr-1 resulted in the development of membrane compromised adherent cells 48 h post-infection (Figure 1A)
AdRFP infection was not toxic (Figure 1A) and red fluorescent protein (RFP) was robustly expressed by cardiac fibroblasts (Figure 1B)
Summary
Cardiac fibroblasts are the predominant cell type (by number) in healthy heart tissue [1] secreting structural collagen, providing an extracellular matrix and supporting the function of contractile cardiomyocytes [2,3,4]. In addition to the role played by cardiomyocytes, fibroblasts are intrinsically involved in processes that lead to heart failure [5]. Fibroblasts play a key role in remodeling of the left ventricle which leads to dilatation and subsequent heart failure [6,7]. A pivotal cardioprotective role has been demonstrated for fibroblasts in myocardial hypertrophy and the prevention of heart failure [10]. Migrate and remodel the interstitium by modulating the secretion of extracellular matrix components and matrix metalloproteinases with multiple signaling cascades controlling
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