Negative regulation of the human atrial natriuretic peptide gene by 1,25-dihydroxyvitamin D3.
We have examined the effect of 1,25-dihydroxyvitamin D3 on the promoter activity of the atrial natriuretic peptide (ANP) gene in cultured neonatal rat atrial myocytes. In acute transfection studies 1,25-dihydroxyvitamin D3 inhibited the expression of a human ANP (hANP) promoter-driven chloramphenicol acetyltransferase reporter (-1150 hANP CAT) in a dose-dependent fashion (10(-10)-10(-8) M). When an expression vector for the vitamin D receptor (VDR) (pSVL-VDR) was introduced together with the reporter plasmid, there was a significant ligand-dependent amplification of the vitamin D-dependent inhibition. Deletion analysis of the 5'-flanking sequence localized the suppressible promoter sequence to within 104 base pairs of the transcription start site of the hANP gene. Thyroid hormone, glucocorticoid, estrogen, and retinoic acid receptor were incapable of mimicking the VDR-dependent inhibition. Retinoid X receptor, on the other hand, effected a significant reduction in hANP promoter activity which was at least additive with that produced by the liganded VDR. The VDR-dependent inhibition displayed promoter selectivity. Both the SV40 promoter and a conventional vitamin D response element linked to a truncated SV40 promoter were activated by the liganded vitamin D receptor, whereas the Rous sarcoma virus promoter was unaffected. On the other hand, the cardiac-specific troponin T promoter was suppressed in a fashion similar to ANP. These findings imply a potentially important role for vitamin D3 in the regulation of gene transcription in myocardial cells.
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Metabolic Research Unit, University of California, San Francisco 94143.
Gardner
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D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis* / Q000235:genetics*; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006325:Heart Atria; D006801:Humans; D009206:Myocardium / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D051381:Rats; D018167:Receptors, Calcitriol / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins / Q000096:biosynthesis; D047488:Retinoid X Receptors; D012176:Retinoids / Q000378:metabolism; D017384:Sequence Deletion; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D016755:Proto-Oncogene Proteins c-jun; D018167:Receptors, Calcitriol; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D004533:Egtazic Acid; D009320:Atrial Natriuretic Factor; D015500:Chloramphenicol O-Acetyltransferase; D002117:Calcitriol; D002118:Calcium