title: 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.
abstract: 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.
authors.affiliation: Cardiovascular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ont., Canada K1Y 4W7.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Ma
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Ogawa
authors.forename: Adolfo J
authors.initials: AJ
authors.lastname: de Bold
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis*; D003720:Densitometry; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology*; D009206:Myocardium / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis*; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014180:Transplantation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D007093:Imidazoles; D007375:Interleukin-1; D010455:Peptides; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020097:Natriuretic Peptide, Brain; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580