INHIBITORY EFFORT OF W-3 PUFAS ON CARDIAC FIBROSIS

Sanford Research/Usd, Fargo SD

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this proposal is to define the therapeutic effect of omega3 polyunsaturated fatty acids n3 PUFAs on cardiac fibrosis, and understand the underlying mechanism of this beneficial effect. Heart failure is the leading cause of hospitalization in patients older than 65 years and affects roughly 5 million persons in the United States. Therefore, heart failure is an important contributor to morbidity, mortality, and health care costs, and there remains a need to discover new treatments. Myocardial fibrosis is a fundamental pathologic process in heart failure. It occurs in a number of pathological processes. In response to hemodynamic stress, the heart undergoes cardiac myocyte remodeling and extracellular matrix remodeling that involves transformation of fibroblasts into myofibroblasts and high level expression of extracellular matrix proteins which lead to interstitial fibrosis 4.TGF beta1 induced transformation of cardiac fibroblasts into myofibroblasts is critical to the production and deposition of collagen and plays an important role in extracellular matrix remodeling during the progression of cardiac dysfunction and heart failure. Omega3 polyunsaturated fatty acids n3 PUFAs especially eicosapentaenoic acid EPA docosahexaenoic acid DHA have beneficial effects on cardiovascular diseases including coronary heart disease, arrhythmia, thrombosis, cardiac hypertrophy and sudden cardiac death. In the heart, n3 PUFAs increase the levels of cGMP, which plays a counter regulatory role against cardiac fibrosis. However, there is little information regarding the effects of n3 PUFAs on cardiac fibrosis or cardiac fibroblasts. Preliminary data from our lab demonstrated that dietary supplementation with fish oil can significantly inhibit cardiac fibrosis and improve cardiac function in mice after pressure overload. In addition, our in vitro studies in adult mouse cardiac fibroblasts suggested that DHA and EPA effectively suppress the TGF beta1 induced transformation of cardiac fibroblasts into myofibroblasts thereby reducing collagen production. Consequently, we have identified a new potentially beneficial effect of n3 PUFAs. This proposal will test the hypothesis that n3 PUFAs inhibit cardiac fibrosis and preserve cardiac function by preventing TGF beta1 induced cardiac fibroblast transformation and proliferation through activation of the cGMP and PKG pathway.