Omega-3 Fatty Acids Prevent Pressure Overload–Induced Cardiac Fibrosis Through Activation of Cyclic GMP/Protein Kinase G Signaling in Cardiac Fibroblasts

Study Questions:

What are the effects of omega-3 polyunsaturated fatty acids (PUFAs) on cardiac fibrosis?


The investigators assessed left ventricular fibrosis and pathology in mice subjected to transverse aortic constriction after the consumption of a fish oil or a control diet. Cell proliferation was determined by the counting of living cells. Collagen synthesis was measured by incorporation of 3H-proline. Means were compared by one-way or two-way ANOVA followed by the Tukey post-hoc test or Dunnett post-hoc test, as appropriate.


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 (EPA) and docosahexaenoic acid (DHA) increased cyclic GMP levels and blocked cardiac fibroblast transformation, proliferation, and collagen synthesis. EPA and DHA blocked phospho-Smad2/3 nuclear translocation. DT3, a protein kinase G inhibitor, blocked the antifibrotic effects of EPA and DHA. EPA and DHA increased phosphorylated endothelial nitric oxide synthase and endothelial nitric oxide synthase protein levels and nitric oxide production.


The authors concluded that 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.


In the present study, omega-3 PUFAs decreased pressure overload–induced cardiac fibrosis by 63% and consequently preserved cardiac function without changing the blood pressure or pressure gradients. These results suggest an antifibrotic effect of omega-3 PUFAs that is independent of afterload. One of the main causes of diastolic heart failure is cardiac fibrosis, and at present, no effective therapies are available to prevent or treat cardiac fibrosis. Given the beneficial effects of omega-3 in this animal model, and its reported safety, it would seem reasonable to assess the therapeutic effect of omega-3 PUFAs on cardiac fibrosis and diastolic heart failure in a clinical trial.

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Nonstatins, Acute Heart Failure, Chronic Heart Failure, Heart Failure and Cardiac Biomarkers, Diet

Keywords: Smad2 Protein, Heart Failure, Diastolic, Biological Markers, Fish Oils, Fibroblasts, Dietary Supplements, Transforming Growth Factors, Fatty Acids, Omega-3, Cyclic GMP-Dependent Protein Kinases, Blood Pressure, United States

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