INHIBITORY EFFORT OF W-3 PUFAS ON CARDIAC FIBROSIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这项建议的目的是确定omega3多不饱和脂肪酸n3多不饱和脂肪酸对心脏纤维化的治疗效果，并了解这种有益效果的潜在机制。心力衰竭是65岁以上患者住院的主要原因，在美国大约有500万人受到影响。因此，心力衰竭是导致发病率、死亡率和医疗费用的重要因素，仍然需要发现新的治疗方法。心肌纤维化是心力衰竭的一个基本病理过程。它发生在许多病理过程中。作为对血流动力学应激的响应，心脏经历了心肌细胞重塑和细胞外基质重塑，包括成纤维细胞向肌成纤维细胞的转化和细胞外基质蛋白的高水平表达，从而导致间质纤维化4.转化生长因子β1诱导的心脏成纤维细胞向肌成纤维细胞的转化是胶原产生和沉积的关键，在心功能不全和心力衰竭的发展过程中，细胞外基质重塑起重要作用。欧米茄3多不饱和脂肪酸n3多不饱和脂肪酸，特别是二十碳五烯酸、EPA、二十二碳六烯酸、DHA对冠心病、心律失常、血栓形成、心肌肥厚和心脏性猝死等心血管疾病具有良好的治疗作用。在心脏中，n3多不饱和脂肪酸增加cGMP的水平，cGMP起到对抗心脏纤维化的反向调节作用。然而，关于n3多不饱和脂肪酸对心脏纤维化或心脏成纤维细胞的影响的信息很少。我们实验室的初步数据表明，饮食中添加鱼油可以显着抑制压力超负荷后小鼠的心脏纤维化，改善心功能。此外，我们在成年小鼠心脏成纤维细胞上的体外研究表明，DHA和EPA有效地抑制了转化生长因子β1诱导的心脏成纤维细胞向肌成纤维细胞的转化，从而减少了胶原的产生。因此，我们已经确定了n3多不饱和脂肪酸的一个新的潜在的有益作用。该方案将验证n3多不饱和脂肪酸通过激活cGMP和PKG通路，阻止转化生长因子β1诱导的心脏成纤维细胞转化和增殖，从而抑制心脏纤维化和保护心功能的假说。

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.