Adrenergic regulation of rat FGF-2 gene expression in the heart

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Detillieux, Karen A.
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Fibroblast growth factor-2 (FGF-2) is a potent ubiquitous, multifunctional peptide growth factor. The myocardium releases FGF-2 with every contraction through transient disruptions in the sarcolemma of cardiac myocytes. Such release of FGF-2 can be increased with adrenergic stimulation. This led to the hypothesis that 'de novo' synthesis of FGF-2 may accompany an induced increase in its release, specifically by adrenergic regulation at the transcriptional level. The 5'-flanking region of the rat FGF-2 gene has been cloned in our laboratory. The rat FGF-2 promoter has no TATA box and instead contains G/C-rich regions typical of a housekeeping gene. FGF-2 gene expression was increased by norepinephrine (NE) after 6 h, specifically and primarily through _1-adrenergic receptors. Deletion analysis of the 1,058 bp of rat FGF-2 5'-flanking DNA showed that an increase in FGF-2 transcription using phenylephrine (PE, an _1-specific agonist) for 48 h could be elicited with only 313 bp of upstream sequence. This deletion excluded an A/G-rich region containing a tandem repeat of an 8 bp element (5'-AGGGAGGG-3 ') which is similar to a phenylephrine-responsive element in the rat ANF promoter. In two lines of transgenic mice into which the FGF-2/luciferase hybrid gene had been introduced, intraperitoneal injection of PE increased luciferase after 6 h. In conclusion, these studies demonstrated that 1,058 bp of rat FGF-2 5' flanking DNA was sufficient to invoke a positive response in cardiac myocytes to catecholamine stimulation specifically through _1-adrenergic receptors, and that this response occurred ' in vitro,' independently of myocyte contraction and Ca2+ influx, as well as 'in vivo' in the adult heart. The A/G-rich region does carry enhancer activity and does bind nuclear protein with high affinity and specificity. The relationship between adrenergic stimulation and a role for FGF-2 in responding to physiological stress is discussed. (Abstract shortened by UMI.)