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 t he degree of left ventricular dysfunction. Our previous in vitro work using transiently transfected neonatal rat cardiac myocytes has shown that the h uman BNP (hBNP) promoter, in particular a region extending from -127 to -40 relative to the start site of transcription, is more active in cardiac myo cytes than in fibroblasts. To study tissue-specific and transcriptional reg ulation of the hBNP gene in vivo, we generated transgenic mice containing t he proximal hBNP promoter (-408 to +100) coupled to a luciferase reporter g ene. In four lines of transgenic mice, luciferase activity was similar to 3 3- to 100-fold higher in the heart than in other tissues, including the who le brain. To test whether the transgene responded to a pathophysiological s timulus, we induced infarction by coronary artery ligation. Luciferase acti vity was fivefold higher in the infarcted region of the left ventricle at 4 8 h than in sham-operated animals and remained elevated for 4 wk. Endogenou s BNP mRNA was similarly increased in the infarcted hearts of a separate gr oup of mice. We conclude that 1) the proximal 408-bp region of the hBNP pro moter confers cardiac-specific expression and 2) myocardial infarction acti vates 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 ge ne in vivo.