Mechanisms of Reduced Heart Failure Pathogenesis with Phytochemical Intake

描述（由申请人提供）：目前，对富含植物化学物质的饮食对高血压相关心力衰竭影响的机制理解非常有限。我们使用添加冻干全葡萄粉的日粮来模拟富含植物化学物质的日粮。初步研究表明，在达尔盐敏感（Dahl- ss）高血压相关性心力衰竭大鼠模型中，富含葡萄的饮食可减少心脏氧化损伤、肥厚、纤维化和心力衰竭。然而，这些影响的机制尚不清楚。广泛关注的葡萄植物化学物质包括花青素、黄烷醇（儿茶素、表儿茶素、槲皮素）和二苯乙烯（白藜芦醇）。为了阐明其机制，我们现在将比较全葡萄粉与含量匹配的分离植物化学物质对Dahl-SS大鼠心力衰竭发病机制的影响。植物化学物质可以激活过氧化物酶体增殖激活受体（PPAR）。PPAR异构体可以减少nfkb相关炎症，心脏PPAR异构体在心力衰竭时下调。植物化学物质可激活NF-E2 p45相关因子（Nrf2）和酚反应性芳烃受体（AhR），刺激抗氧化防御相关基因转录。我们的三个中心假设是，在盐饲养的Dahl-SS大鼠中，1)全葡萄在减少心脏纤维化和改善心脏指数方面优于分离的植物化学物质，2)全葡萄在心脏AhR和Nrf2激活和抗氧化基因表达方面优于分离的植物化学物质，3)全葡萄在增强心脏PPAR激活和降低NFkB激活方面优于分离的植物化学物质。我们将通过以下两个目标来检验中心假设：（目的1）比较治疗对心脏内源性抗氧化防御的影响。检测心脏AhR和Nrf2核易位的变化以及与抗氧化防御相关的XRE和re相关基因组靶点的表达；（目的2）比较治疗对心脏ppar和NFkB信号的影响。检测心脏PPAR异构体活性的变化和PPAR靶基因的表达。测量核NFkB及其与炎症和纤维化相关的基因组靶点的表达。我们的长期目标是以葡萄为模型，阐明分离植物化学物质与富含植物化学物质的天然食物的相对心脏作用。拟议的研究具有创新性，因为它们超越了短暂的影响，并检查了生理相关的、富含植物化学物质的饮食或分离的植物化学补充剂对健康和患病心脏的累积的心脏影响。这项研究对公共卫生具有重要的转化潜力，因为研究结果可以提高人们对膳食和膳食补充剂预防高血压相关心脏病理的价值的认识。此外，我们的比较研究可能表明，植物化学物质的种类提供优越的心脏保护。

DESCRIPTION (provided by applicant): Currently, mechanistic understanding of the impact of phytochemical-rich diets on hypertension-associated heart failure is very limited. We used diets supplemented with freeze-dried whole grape powder to model a phytochemical-enriched diet. Preliminary studies show that a grape-enriched diet reduced cardiac oxidative damage, hypertrophy, and fibrosis and heart failure in the Dahl Salt-Sensitive (Dahl-SS) rat model of hypertension-associated heart failure. However, mechanisms of these effects remain unknown. Grape phytochemicals of broad interest include anthocyanins, flavanols (catechin, epicatechin, quercetin), and stilbenes (resveratrol). To elucidate mechanism, we will now compare the effects of whole grape powder to content-matched, isolated phytochemicals on Dahl-SS rat heart failure pathogenesis. Phytochemicals can activate peroxisome proliferator-activating receptors (PPAR). PPAR isoforms can reduce NFkB-related inflammation, and cardiac PPAR isoforms are down-regulated with heart failure. Phytochemicals can activate the NF-E2 p45-related factor (Nrf2) and the phenol-responsive Aryl-hydrocarbon receptor (AhR) which stimulates the gene transcription related to antioxidant defense. Our three-pronged central hypothesis is that in salt-fed Dahl-SS rats, 1) whole grape is superior to isolated phytochemicals in reducing cardiac fibrosis and improved cardiac index, 2) whole grape is superior to isolated phytochemicals towards cardiac AhR and Nrf2 activation and antioxidant gene expression, and 3) whole grape is superior to isolated phytochemicals towards enhanced cardiac PPAR activation and reduced NFkB activation. We will test the central hypothesis by the following two aims: (Aim 1) Compare Treatment Effects on Cardiac Endogenous Antioxidant Defense. Examine changes in cardiac AhR and Nrf2 nuclear translocation and the expression of XRE and ARE-related genomic targets related to antioxidant defense; (Aim 2) Compare Treatment Effects on Cardiac PPARs and Cardiac NFkB signaling. Examine changes in cardiac PPAR isoform activity and the expression of PPAR target genes. Measure nuclear NFkB and the expression of its genomic targets related to inflammation and fibrosis. Our long-term goal is to elucidate the relative cardiac effects of isolated phytochemical versus phytochemical- rich whole foods, using grapes as a model. The proposed studies are innovative because they go beyond transient effects and examine the accumulated, cardiac effects of a physiologically relevant, phytochemical- enriched diet or isolated phytochemical supplements on both healthy and diseased hearts. This proposed study is significant for public health with translational potential because findings could improve knowledge of the value of dietary and dietary supplement approaches for prevention of hypertension-associated cardiac pathology. In addition, our comparative studies may suggest classes of phytochemicals that provide superior cardioprotection. PUBLIC HEALTH RELEVANCE: Heart failure is a significant health burden that principally affects our aging population. The effect of diet on heart failure is poorly understood. Our long-term goal is to advance knowledge on the relative cardiac benefits of isolated phytochemical supplements versus phytochemical-rich whole foods.