INHIBITORY EFFORT OF W-3 PUFAS ON CARDIAC FIBROSIS

W-3 PUFA 对心脏纤维化的抑制作用

• 批准号: 8168345
• 负责人: Daguang Wang
• 金额: $ 9.21万
• 依托单位: SANFORD RESEARCH/USD
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168345
• 关键词: Adult; Affect; Arrhythmia; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Collagen; Computer Retrieval of Information on Scientific Projects Database; Coronary heart disease; Cyclic GMP; Data; Deposition; Dietary Supplementation; Docosahexaenoic Acids; Eicosapentaenoic Acid; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Fish Oils; Functional disorder; Funding; Goals; Grant; Health Care Costs; Heart; Heart Hypertrophy; Heart failure; Hospitalization; In Vitro; Institution; Lead; Morbidity - disease rate; Mus; Myocardial; Myofibroblast; Pathologic Processes; Pathway interactions; Persons; Play; Polyunsaturated Fatty Acids; Production; Research; Research Personnel; Resources; Role; Source; Stress; Testing; Therapeutic Effect; Thrombosis; United States; United States National Institutes of Health; hemodynamics; human TGFB1 protein; human old age (65+); improved; interstitial; mortality; older patient; pressure; prevent; response; sudden cardiac death

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该建议的目的是定义omega3多不饱和脂肪酸N3 PUFAS对心脏纤维化的治疗作用，并了解这种有益作用的潜在机制。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。因此，心力衰竭是导致发病率，死亡率和医疗保健成本的重要原因，并且仍然需要发现新的治疗方法。心肌纤维化是心力衰竭的基本病理过程。它发生在许多病理过程中。为了应对血液动力学压力，心脏经历心肌细胞的重塑和细胞外基质重塑，涉及将成纤维细胞转化为肌纤维细胞和高水平的细胞外基质蛋白的高表达胶原蛋白并在心脏功能障碍和心力衰竭进展过程中在细胞外基质重塑中起重要作用。 omega3多不饱和脂肪酸N3 PUFA，尤其是eicosapentaenoic aca epa docahecosahexaenoic dha对包括冠心病，心律失常，血栓形成，心血管，心脏肥大和突然心脏死亡的心血管疾病对心血管疾病具有有益的作用。在心脏中，N3 PUFA会增加CGMP的水平，CGMP对心脏纤维化起着相反的调节作用。但是，关于N3 PUFAS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，用鱼油补充饮食可以显着抑制心脏纤维化并改善压力超负荷后小鼠的心脏功能。此外，我们对成年小鼠心脏成纤维细胞的体外研究表明，DHA和EPA有效抑制了TGF Beta1诱导心脏成纤维细胞转化为肌纤维细胞，从而减少了胶原蛋白的产生。因此，我们已经确定了N3 Pufas的新潜在有益作用。该建议将检验以下假设：N3 PUFA通过防止TGF Beta1诱导心脏成纤维细胞转化和通过激活CGMP和PKG途径来抑制心脏纤维化并保持心脏功能。