Omega-3 Fatty Acids and Heart Failure

描述(申请人提供)：尽管积极的诊断和治疗，高血压仍然是一个主要的临床问题，经常导致慢性心力衰竭(HF)鱼油(二十碳五烯酸(EPA)和十二烷基己酸(DHA))和一些植物(亚麻籽或菜籽油中的1-亚麻酸(ALA))中发现的omega-3脂肪酸可预防高血压患者的左心室肥厚和心力衰竭的发展。我们最近观察到，在高血压大鼠的饮食中添加鱼油(相当于能量消耗的2.8%，EPA+DHA)可以减轻高血压大鼠的左心室肥厚，防止左心室功能障碍的发展。HF导致PPAR调节基因(控制能量代谢相关蛋白的表达)下调，降低脂肪酸代谢，损害线粒体功能。Omega-3脂肪酸是PPAR的有效配体，因此可以激活心脏基因的表达，改善线粒体代谢和心脏功能。摄入鱼油还增加了血浆中心脏保护激素脂联素的含量，我们发现这与预防压力超负荷大鼠的心功能障碍有关。这项应用的目标是了解omega-3脂肪酸如何影响压力超负荷高血压患者心力衰竭的发展和进展。研究将使用已建立的左心室肥厚和心力衰竭的主动脉带模型进行体内研究。我们的主要假设是，omega 3FA(来自鱼油或ALA)将通过增加PPAR调节基因的表达和增加血清脂联素浓度来减轻LVH和预防心力衰竭。研究的两个具体目的是：1)研究膳食omega 3FA(鱼油(EPA+DHA)或亚麻籽油(ALA))对慢性主动脉缩窄所致高血压大鼠心力衰竭发生的影响。此外，还将评估omega 3FA逆转已建立的HF的能力。2)确定增加脂联素是否对补充omega 3FA所观察到的LVH和HF的预防至关重要。WT和脂联素基因敲除的小鼠将接受主动脉缩窄，并喂以正常饲料或添加鱼油I-3FAs的饲料。超声心动图和左心室压力-容量测量将用于评估肥厚和心力衰竭的发展，并将测量基因表达和代谢酶的变化。公共卫生相关性尽管进行了积极的诊断和治疗，高血压仍然是一个主要的临床问题，并经常导致慢性心力衰竭。在鱼油和一些植物中发现的omega-3脂肪酸可以防止心力衰竭的发展。这项应用的目标是了解omega-3脂肪酸如何影响高血压患者心力衰竭的发展和进展。

DESCRIPTION (provided by applicant): Despite aggressive diagnosis and treatment, hypertension remains a major clinical problem and frequently leads to chronic heart failure (HF) The omega-3 fatty acids found in fish oils (eicosapentanoic acid (EPA) and docohexanoic acid (DHA)) and in some plants (1-linolenic acid (ALA) in flax seed or canola oil) may prevent the development of left ventricular (LV) hypertrophy and HF in hypertension. We recently observed that the addition of fish oil (2.8% of energy consumption as EPA+DHA) to the diet of rats subjected to hypertension attenuated LV hypertrophy and prevented the development of LV dysfunction. HF causes down-regulation of peroxisome proliferator activated receptor (PPAR)-regulated genes (which control expression of proteins involved in energy metabolism) and decreases fatty acid metabolism and impairs mitochondrial function. Omega-3 fatty acids are potent ligands for PPARs, and thus could activate cardiac gene expression and improve mitochondrial metabolism and cardiac function. Fish oil intake also increased the cardioprotective hormone adiponectin in plasma, which we found correlated with prevention of cardiac dysfunction in pressure overloaded rats. The goal of this application is to understand how omega-3 fatty acids affect the development and progression of HF in pressure-overload hypertension. Studies will be performed in vivo using well established aortic banding models of LV hypertrophy and HF. Our primary hypothesis is that omega 3FA (either from fish oil or ALA) will attenuate LVH and prevent HF due to increased expression of PPAR-regulated genes and increased serum adiponectin concentration. The two Specific Aims are: 1)Determine the effects of dietary omega 3FA (from either fish oil (EPA+DHA) or flax seed oil (ALA)) on the development of HF during hypertension induced by chronic aortic banding in rats. In addition, the ability of omega 3FA to reverse established HF will be assessed. 2) Determine if increased adiponectin is essential for the prevention of LVH and HF observed with omega 3FA supplementation. WT and adiponectin knock out mice will be subjected to aortic banding and fed either normal chow or chow supplemented with I-3FAs from fish oil. Echocardiography and LV pressure-volume measurements will be used to assess development of hypertrophy and HF, and alterations in gene expression and metabolic enzymes will be measured. PUBLIC HEALTH RELEVANCE Despite aggressive diagnosis and treatment, hypertension remains a major clinical problem and frequently leads to chronic heart failure. The omega-3 fatty acids found in fish oils and in some plants may prevent the development heart failure. The goal of this application is to understand how omega-3 fatty acids affect the development and progression of HF in hypertension.