Mechanisms of Reduced Heart Failure Pathogenesis with Phytochemical Intake

摄入植物化学物质减少心力衰竭发病机制

• 批准号: 8045087
• 负责人: Steven F Bolling
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045087
• 关键词: Affect; Alternative Medicine; American; Anthocyanins; Antioxidants; Aryl Hydrocarbon Receptor; Binding; Bioavailable; Blood Pressure; Cardiac; Cardiovascular system; Catechin; Comparative Study; Dahl Hypertensive Rats; Data; Diet; Elements; Fibrosis; Flavanol; Food; Freeze Drying; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Genomics; Glutathione; Goals; Grapes; Health; Heart; Heart Hypertrophy; Heart failure; Hypertension; Hypertrophy; In Vitro; Inflammation; Intake; Knowledge; Lead; Measures; Modeling; Nuclear; Nuclear Translocation; Oxidation-Reduction; Pathogenesis; Pathology; Pattern; Peroxisome Proliferator-Activated Receptors; Phenols; Phytochemical; Powder dose form; Prevention approach; Preventive; Protein Isoforms; Public Health; Quercetin; Rat-1; Receptor Activation; Reducing diet; Relative (related person); Response Elements; Resveratrol; Signal Transduction; Sodium Chloride; Stilbenes; Testing; aging population; dietary supplements; epicatechin; feeding; fruits and vegetables; hypertension prevention; improved; in vivo; indexing; innovation; interest; oxidative damage; polyphenol; transcription factor; treatment effect

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.

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。我们使用的饮食补充冻干全葡萄粉，以模拟植物化学物质丰富的饮食。初步研究表明，富含葡萄的饮食减少了高血压相关心力衰竭的达尔盐敏感（Dahl-SS）大鼠模型中的心脏氧化损伤、肥大、纤维化和心力衰竭。然而，这些影响的机制仍然未知。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）和芪（白藜芦醇）。为了阐明机制，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物激活受体（过氧化物酶体增殖物激活受体）。过氧化物酶体增殖物激活物受体亚型可以减少NF κ B相关的炎症，心脏过氧化物酶体增殖物激活物受体亚型在心力衰竭时下调。植物化学物质可以激活NF-E2 p45相关因子（Nrf 2）和酚响应性芳烃受体（AhR），从而刺激与抗氧化防御相关的基因转录。我们的三管齐下的中心假设是，在盐喂养的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上级分离的植物化学物质，2）全葡萄在心脏AhR和Nrf 2活化和抗氧化基因表达方面上级分离的植物化学物质，3）全葡萄在增强心脏PPAR活化和减少NF κ B活化方面上级分离的植物化学物质。我们将通过以下两个目的来检验中心假设：（目的1）比较对心脏内源性抗氧化防御的治疗效果。检查心脏AhR和Nrf 2核转位的变化以及与抗氧化防御相关的XRE和ARE相关基因组靶标的表达;（目的2）比较对心脏PPARs和心脏NFkB信号传导的治疗效果。检查心脏过氧化物酶体增殖物激活受体亚型活性和过氧化物酶体增殖物激活受体靶基因表达的变化。测量核NFkB及其与炎症和纤维化相关的基因组靶标的表达。我们的长期目标是以葡萄为模型，阐明单独的植物化学物质与富含植物化学物质的天然食物对心脏的相对影响。拟议的研究是创新的，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物质补充剂对健康和患病心脏的累积心脏影响。这项拟议的研究对具有转化潜力的公共卫生具有重要意义，因为研究结果可以提高对膳食和膳食补充剂方法预防高血压相关心脏病理学价值的认识。此外，我们的比较研究可能会建议提供上级心脏保护的植物化学物质的类别。 公共卫生相关性：心力衰竭是一个重大的健康负担，主要影响我们的老龄化人口。饮食对心力衰竭的影响知之甚少。我们的长期目标是推进关于孤立的植物化学补充剂与富含植物化学物质的全食品的相对心脏益处的知识。