Omega-3 Fatty Acids and Heart Failure

描述（申请人提供）：尽管有积极的诊断和治疗，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）。鱼油中发现的omega-3脂肪酸（二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）），并且在一些植物中（亚麻籽或菜籽油中的1-亚麻酸（ALA））可以预防高血压患者左心室（LV）肥大和HF的发生。我们最近观察到，在高血压大鼠的饮食中添加鱼油（EPA+DHA占能量消耗的2.8%）可减轻LV肥大并防止LV功能障碍的发展。HF导致过氧化物酶体增殖物激活受体（PPAR）调节基因（控制参与能量代谢的蛋白质表达）下调，并降低脂肪酸代谢和损害线粒体功能。ω-3脂肪酸是PPARs的有效配体，因此可以激活心脏基因表达，改善线粒体代谢和心脏功能。鱼油摄入量也增加了血浆中的心脏保护激素脂联素，我们发现这与预防压力超负荷大鼠的心功能障碍有关。本申请的目的是了解omega-3脂肪酸如何影响压力超负荷高血压患者HF的发生和进展。将使用完善的LV肥大和HF主动脉缩窄模型在体内进行研究。我们的主要假设是，由于PPAR调节基因的表达增加和血清脂联素浓度增加，欧米茄3FA（来自鱼油或ALA）将减轻LVH并预防HF。这两个具体目标是：1）确定膳食ω-3FA（来自鱼油（EPA+DHA）或亚麻籽油（ALA））对大鼠中由慢性主动脉缩窄诱导的高血压期间HF发展的影响。此外，还将评估omega 3FA逆转已建立的HF的能力。2)确定增加脂联素对于预防补充omega 3FA后观察到的LVH和HF是否至关重要。WT和脂联素敲除小鼠将进行主动脉结扎，并喂食正常食物或补充有来自鱼油的I-3FA的食物。超声心动图和LV压力-容积测量将用于评估肥大和HF的发展，并测量基因表达和代谢酶的变化。 尽管有积极的诊断和治疗，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。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。本申请的目的是了解omega-3脂肪酸如何影响高血压患者HF的发生和进展。

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.