Human cardiac fibroblasts express B-type natriuretic peptide: fluvastatin ameliorates its up-regulation by interleukin-1alpha, tumour necrosis factor-alpha and transforming growth factor-beta.
B-type natriuretic peptide (BNP) is a cardiac hormone, which plays a major role in body fluid and cardiovascular homeostasis. Produced by cardiac ventricles, its expression is highly regulated by various mediators. Canine cardiac fibroblasts have been identified as a source of BNP. Cardiac fibroblasts are key regulators of myocardial structure and function. We treated cultured human adult cardiac fibroblasts (HACF) with 2000 U/ml tumour necrosis factor-alpha (TNF-alpha), 200 U/ml interleukin-1alpha (IL-1alpha) or 50 ng/ml transforming growth factor-beta (TGF-beta) in the presence or absence of 500 nM fluvastatin. N-terminal pro-BNP (Nt-proBNP) concentration was determined by a competitive enzyme immunoassay. RealTime polymerase chain reaction (real-time PCR) was performed to investigate changes in BNP mRNA expression. Nt-proBNP peptide was present in the conditioned media of HACF and incubation with fluvastatin significantly reduced Nt-proBNP peptide levels. Treatment of HACF with TNF-alpha, IL-1alpha or TGF-beta significantly increased Nt-proBNP levels compared with untreated cells. This effect was completely abolished in the presence of fluvastatin. Real-time PCR analysis confirmed these changes at the level of mRNA expression. Our data suggest that cardiac fibroblasts are a potential source of BNP in the human heart. Pro-inflammatory cytokines, associated with ventricular dysfunction and cardiac fibrosis, seem to be major inducers of BNP production in cardiac fibroblasts. This effect can be reverted by a statin. Based on our data, we speculate that elevated plasma BNP levels might not only reflect increased myocardial stretch but also inflammatory and remodelling processes. A possible benefit of statin-induced reduction in BNP production requires further studies.
Jarai
Rudolf
R
Department of Cardiology and Emergency Medicine, Wilhelminenhospital, Vienna, Austria.
Kaun
Christoph
C
Weiss
Thomas W
TW
Speidl
Walter S
WS
Rychli
Kathrin
K
Maurer
Gerald
G
Huber
Kurt
K
Wojta
Johann
J
D000328:Adult; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D000077340:Fluvastatin; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D017370:Interleukin-11 / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis / Q000235:genetics; D053683:Oncostatin M / Q000494:pharmacology; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D017370:Interleukin-11; D053582:Interleukin-1alpha; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D010446:Peptide Fragments; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C109794:pro-brain natriuretic peptide (1-76); D053683:Oncostatin M; D020097:Natriuretic Peptide, Brain; D000077340:Fluvastatin