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J Mol Cell Cardiol. 2004 Apr;36(4):505-13.

Selective upregulation of cardiac brain natriuretic peptide at the transcriptional and translational levels by pro-inflammatory cytokines and by conditioned medium derived from mixed lymphocyte reactions via p38 MAP kinase.

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Cardiovascular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ont., Canada K1Y 4W7.


An increase in circulating brain natriuretic peptide (BNP) but not atrial natriuretic factor (ANF) is observed coincident with cardiac allograft rejection that is reversed upon treatment with anti-lymphocyte therapy suggesting that pro-inflammatory cytokines may uniquely modulate BNP gene expression and secretion. This study tested pro-inflammatory cytokines or conditioned medium (CM) derived from mixed- lymphocyte reaction (MLR) cultures in their ability to modulate ANF or BNP mRNA expression, secretion, as well as BNP promoter activity in cultured neonatal rat cardiocytes. IL-1 beta and TNF-alpha elicited a significant dose- and time-dependent increase in BNP mRNA, and secretion, whereas, ANF mRNA levels and secretion did not change. IL-1 beta and TNF-alpha rapidly increased phosphorylated p38 MAP kinase abundance and activity. Inhibition of p38 MAP kinase with SB203580 abolished IL-1 beta- and TNF-alpha-stimulated increase in BNP mRNA, promoter activity and secretion. MLR-CM in 20%, 50% and 100% proportions increased BNP but not ANF secretion. The MLR-induced increases in BNP secretion were completely abolished by SB203580 pre-treatment. These investigations show that exposure of cultured rat cardiocytes to specific pro-inflammatory cytokines as well as MLR-CM results in the only known instance of upregulation of cardiac BNP at the transcriptional and translational levels without a corresponding increase in ANF gene expression. Furthermore, these effects are dependent on signaling by p38 MAP kinase. In all, the findings reveal a unique dis-coordinated expression of BNP and ANF to inflammatory cytokines and offers an opportunity to better understand the differential regulation of these two cardiac-derived endocrine hormones that share receptors as well as biological properties.

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