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J Biol Chem, Vol. 274, Issue 18, 12819-12826, April 30, 1999

The Role of GATA, CArG, E-box, and a Novel Element in the Regulation of Cardiac Expression of the Na⁺-Ca²⁺ Exchanger Gene

From the Cardiology Division, Department of Medicine, and the Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, South Carolina, 29425-2221

The cardiac Na⁺-Ca²⁺ exchanger (NCX1) is the principal Ca²⁺ efflux mechanism in cardiocytes. The exchanger is up-regulated in both cardiac hypertrophy and failure. In this report, we identify the cis-acting elements that control cardiac expression and -adrenergic up-regulation of the exchanger gene. Deletion analysis revealed that a minimal cardiac promoter fragment from 184 to +172 is sufficient for cardiac expression and -adrenergic stimulation. Mutational analysis revealed that both the CArG element at 80 and the GATA element at 50 were required for cardiac expression. Gel mobility shift assay supershift analysis demonstrated that the serum response factor binds to the CArG element and GATA-4 binds to the GATA element. Point mutations in the 172 E-box demonstrated that it was required for -adrenergic induction. In addition, deletion analysis revealed one or more enhancer elements in the first intron (+103 to +134) that are essential for phenylephrine up-regulation but bear no homology to any known transcription element. Therefore, this work demonstrates that SRF and GATA-4 are critical for NCX1 expression in neonatal cardiomyocytes and that the 172 E-box in addition to a novel enhancer element(s) are required for phenylephrine up-regulation of NCX1 and may mediate its hypertrophic up-regulation.

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