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Cardiovascular Research 2004 62(3):548-557; doi:10.1016/j.cardiores.2004.01.032
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Transcriptional regulation of FGF-2 gene expression in cardiac myocytes

Sarah K Jimeneza, Farah Sheikhb, Yan Jina, Karen A Detillieuxa, Jamit Dhaliwala, Elissavet Kardamic and Peter A Cattini*,a

aDepartment of Physiology, University of Manitoba, 730 William Avenue, Winnipeg, MB, Canada R3E 3J7
bInstitute of Molecular Medicine, University of California San Diego, San Diego, CA, USA
cDepartment of Human Anatomy and Cell Science, University of Manitoba, Canada

* Corresponding author. Tel.: +1-204-789-3696; fax: +1-204-789-3934. Email address: peter_cattini{at}umanitoba.ca

Objective: Fibroblast growth factor-2 (FGF-2) exerts its cardioprotective effect through cell surface receptor signaling and may play a role in the normal maintenance of a healthy myocardium. One mechanism of FGF-2 release from contracting cardiomyocytes is through transient sarcolemmal disruption, with accumulation in the extracellular matrix. Continuous FGF-2 release would require a link to synthesis and, thus, we examined regulation of FGF-2 promoter activity in cardiomyocytes as a potential target for optimizing cardioprotection. Methods and results: To investigate autoregulation, neonatal rat cardiomyocytes, (NRCM), were transfected with ~1 or 0.1 kb of rat FGF-2 promoter sequences linked to luciferase, –1058FGF–2p.luc and –110FGF–2p.luc, and treated with or without FGF-2. FGF-2 promoter activity was significantly increased ~2.5-fold with both genes. The proximal promoter region of rat FGF-2 contains putative binding sites for the early growth response-1 (Egr-1) and stimulating protein 1 (Sp1) transcription factors. Overexpression of Egr-1 and Sp1 increased –1058FGF–2p.luc expression by 4.4- and 8.7-fold, respectively. Mutation of Egr-1 and overlapping Sp1 sites did not blunt the response of –110FGF–2p.luc to FGF-2 treatment but did significantly reduce basal promoter activity. Transgenic mice expressing –1058FGF–2p.luc were treated with isoproterenol (IsP) to increase heart rate and endogenous FGF-2 release. FGF-2 promoter activity was stimulated significantly at 6 h, and increases in both FGF-2 and its receptor mRNA levels were also detected. In contrast, no effect of IsP was seen on –1058FGF–2p.luc or –110FGF–2p.luc in transfected NRCMs. Conclusions: FGF-2 released from cardiomyocytes may act to regulate its own synthesis at the transcriptional level. The mechanism does not appear to require an intact Egr-1 site in the proximal promoter region. This may, however, reflect redundancy in the control of FGF-2 promoter activity as our data support a stimulatory role for Egr-1 and Sp1.

KEYWORDS Cardioprotection; FGF-2; Gene expression; Growth factors; Myocytes

Time for primary review 25 days


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