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

J Cell Mol Med. 2009 Nov-Dec;13(11-12):4415-21. doi: 10.1111/j.1582-4934.2009.00704.x. Epub 2009 Feb 17.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Fatty Acids, Monounsaturated / pharmacology*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Fluvastatin
  • Humans
  • Indoles / pharmacology*
  • Interleukin-11 / pharmacology
  • Interleukin-1alpha / pharmacology*
  • Interleukin-6 / pharmacology
  • Leukemia Inhibitory Factor / pharmacology
  • Myocardium / cytology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Natriuretic Peptide, Brain / biosynthesis
  • Natriuretic Peptide, Brain / genetics
  • Oncostatin M / pharmacology
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Up-Regulation / drug effects*

Substances

  • Fatty Acids, Monounsaturated
  • Indoles
  • Interleukin-11
  • Interleukin-1alpha
  • Interleukin-6
  • Leukemia Inhibitory Factor
  • Peptide Fragments
  • RNA, Messenger
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • pro-brain natriuretic peptide (1-76)
  • Oncostatin M
  • Natriuretic Peptide, Brain
  • Fluvastatin