Inducible regulation of human brain natriuretic peptide promoter in transgenic mice.
Studies have shown that brain natriuretic peptide (BNP) gene expression is rapidly induced in the infarcted heart and that plasma BNP levels reflect the degree of left ventricular dysfunction. Our previous in vitro work using transiently transfected neonatal rat cardiac myocytes has shown that the human BNP (hBNP) promoter, in particular a region extending from -127 to -40 relative to the start site of transcription, is more active in cardiac myocytes than in fibroblasts. To study tissue-specific and transcriptional regulation of the hBNP gene in vivo, we generated transgenic mice containing the proximal hBNP promoter (-408 to +100) coupled to a luciferase reporter gene. In four lines of transgenic mice, luciferase activity was approximately 33- to 100-fold higher in the heart than in other tissues, including the whole brain. To test whether the transgene responded to a pathophysiological stimulus, we induced infarction by coronary artery ligation. Luciferase activity was fivefold higher in the infarcted region of the left ventricle at 48 h than in sham-operated animals and remained elevated for 4 wk. Endogenous BNP mRNA was similarly increased in the infarcted hearts of a separate group of mice. We conclude that 1) the proximal 408-bp region of the hBNP promoter confers cardiac-specific expression and 2) myocardial infarction activates the proximal hBNP promoter in vivo. These data suggest that we have a valid model for the study of basal and inducible regulation of the hBNP gene in vivo.
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Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Wang
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Yang
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Carretero
O A
OA
LaPointe
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MC
D000818:Animals; D001794:Blood Pressure; D015152:Blotting, Northern; D015139:Blotting, Southern; D006321:Heart; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D019076:Transgenes; D014463:Ultrasonography
D020097:Natriuretic Peptide, Brain; D008156:Luciferases