Eicosapentaenoic acid prevents endothelin-1-induced cardiomyocyte hypertrophy in vitro through the suppression of TGF-beta 1 and phosphorylated JNK

Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H835-45. doi: 10.1152/ajpheart.01365.2005. Epub 2006 Feb 24.

Abstract

The cardiovascular benefit of fish oil in humans and experimental animals has been reported. Endothelin (ET)-1 is a well-known cardiac hypertrophic factor. However, although many studies link a fish oil extract, eicosapentaenoic acid (EPA), to cardiac protection, the effects of EPA on cardiac hypertrophy and underlying mechanism(s) are unclear. The present study investigated whether EPA prevents ET-1-induced cardiomyocyte hypertrophy; the potential pathways likely to underlie such an effect were also investigated. Cardiomyocytes were isolated from neonatal rat heart, cultured for 3 days, and then treated for 24 h with vehicle only (control), treated with 0.1 nM ET-1 only, or pretreated with 10 microM EPA and then treated with 0.1 nM ET-1. The cells were harvested, and changes in cell surface area, protein synthesis, expression of a cytoskeletal (alpha-actinin) protein, and cell signaling were analyzed. ET-1 induced a 97% increase in cardiomyocyte surface area, a 72% increase in protein synthesis rate, and an increase in expression of alpha-actinin and signaling molecule [transforming growth factor-beta 1 (TGF-beta 1), c-Jun NH2-terminal kinase (JNK), and c-Jun]. Development of these ET-1-induced cellular changes was attenuated by EPA. Moreover, the hypertrophied cardiomyocytes showed a 1.5- and a 1.7-fold increase in mRNA expression of atrial and brain natriuretic peptides, the classical molecular markers of cardiac hypertrophy, respectively; these changes were also suppressed by EPA. Here we show that ET-1 induces cardiomyocyte hypertrophy and expression of hypertrophic markers, possibly mediated by JNK and TGF-beta 1 signaling pathways. These ET-1-induced effects were blocked by EPA, a major fish oil ingredient, suggesting that fish oil may have beneficial protective effects on cardiac hypertrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Atrial Natriuretic Factor / physiology
  • Biomarkers
  • Blotting, Western
  • Cardiomegaly / chemically induced*
  • Cardiomegaly / pathology
  • Cardiomegaly / prevention & control*
  • Cell Size
  • Cells, Cultured
  • Eicosapentaenoic Acid / pharmacology*
  • Endothelin-1 / antagonists & inhibitors*
  • Endothelin-1 / biosynthesis
  • Endothelin-1 / toxicity*
  • Enzyme-Linked Immunosorbent Assay
  • Fluorescent Antibody Technique
  • Immunohistochemistry
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Myocytes, Cardiac / pathology*
  • Natriuretic Peptide, Brain / physiology
  • Phosphorylation
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta1

Substances

  • Biomarkers
  • Endothelin-1
  • RNA, Messenger
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Natriuretic Peptide, Brain
  • Atrial Natriuretic Factor
  • Eicosapentaenoic Acid
  • JNK Mitogen-Activated Protein Kinases