title: Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts.
abstract: BACKGROUND
  Omega-3 polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) from fish oil ameliorate cardiovascular diseases. However, little is known about the effects of ω-3 polyunsaturated fatty acids on cardiac fibrosis, a major cause of diastolic dysfunction and heart failure. The present study assessed the effects of ω-3 polyunsaturated fatty acids on cardiac fibrosis.
  
  
  RESULTS
  We assessed left ventricular fibrosis and pathology in mice subjected to transverse aortic constriction after the consumption of a fish oil or a control diet. In control mice, 4 weeks of transverse aortic constriction induced significant cardiac dysfunction, cardiac fibrosis, and cardiac fibroblast activation (proliferation and transformation into myofibroblasts). Dietary supplementation with fish oil prevented transverse aortic constriction-induced cardiac dysfunction and cardiac fibrosis and blocked cardiac fibroblast activation. In heart tissue, transverse aortic constriction increased active transforming growth factor-β1 levels and phosphorylation of Smad2. In isolated adult mouse cardiac fibroblasts, transforming growth factor-β1 induced cardiac fibroblast transformation, proliferation, and collagen synthesis. Eicosapentaenoic acid and docosahexaenoic acid increased cyclic GMP levels and blocked cardiac fibroblast transformation, proliferation, and collagen synthesis. Eicosapentaenoic acid and docosahexaenoic acid blocked phospho-Smad2/3 nuclear translocation. DT3, a protein kinase G inhibitor, blocked the antifibrotic effects of eicosapentaenoic acid and docosahexaenoic acid. Eicosapentaenoic acid and docosahexaenoic acid increased phosphorylated endothelial nitric oxide synthase and endothelial nitric oxide synthase protein levels and nitric oxide production.
  
  
  CONCLUSIONS
  Omega-3 fatty acids prevent cardiac fibrosis and cardiac dysfunction by blocking transforming growth factor-β1-induced phospho-Smad2/3 nuclear translocation through activation of the cyclic GMP/protein kinase G pathway in cardiac fibroblasts.
authors.affiliation: Cardiovascular Health Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA.
authors.forename: Jinghai
authors.initials: J
authors.lastname: Chen
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Shearer
authors.forename: Quanhai
authors.initials: Q
authors.lastname: Chen
authors.forename: Chastity L
authors.initials: CL
authors.lastname: Healy
authors.forename: April J
authors.initials: AJ
authors.lastname: Beyer
authors.forename: Vijaya B
authors.initials: VB
authors.lastname: Nareddy
authors.forename: A Martin
authors.initials: AM
authors.lastname: Gerdes
authors.forename: William S
authors.initials: WS
authors.lastname: Harris
authors.forename: Timothy D
authors.initials: TD
authors.lastname: O'Connell
authors.forename: Dajun
authors.initials: D
authors.lastname: Wang
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019587:Dietary Supplements; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D006352:Heart Ventricles / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000473:pathology* / Q000517:prevention & control*; D020257:Ventricular Remodeling; D014810:Vitamin E / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D015525:Fatty Acids, Omega-3; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D014810:Vitamin E; C082097:tocotrienol, delta; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP