Effects of Cocoa Flavonols on Myocardial Infarction Size and Post-Injury Injury

可可黄酮醇对心肌梗死面积和损伤后损伤的影响

• 批准号: 7694384
• 负责人: Francisco J Villarreal
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7694384
• 关键词: Address; Adhesions; Adhesives; Adverse effects; Alcohol consumption; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Asians; Attention; Beverages; Blood; Blood Platelets; Blood Vessels; Blood specimen; Buffers; Cardiac; Cardiovascular Diseases; Cardiovascular system; Catechin; Cells; Chocolate; Cicatrix; Cocoa Powder; Complementary and alternative medicine; Consumption; Data; Diabetes Mellitus; Disease; Dose; Eicosanoids; Endothelial Cells; Environmental Risk Factor; Epidemiology; Flavanol; Flavonoids; Flavonols; Food; Fruit; Gelatinase B; General Population; Generations; Genetic; Goals; Healed; Heart; Heart Injuries; Hispanics; Human; Incidence; Infarction; Infiltration; Inflammation; Inflammatory; Ingestion; Injury; Insulin; Insulin Resistance; Ischemia; Knockout Mice; Leukocytes; Life; Link; Longevity; Low Density Lipoprotein oxidation; Matrix Metalloproteinases; Mediating; Mediterranean Diet; Mind; Minority; Modeling; Myocardial; Myocardial Ischemia; Nitric Oxide; Nomads; Obesity; Organ; Outcome; Panama; Physical activity; Plants; Plasma; Play; Preparation; Process; Production; Proteins; Rattus; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Reporting; Risk Factors; Role; Scheme; Skeletal Muscle; Structure; Tea; Testing; Time; Tissues; Transfusion; Vasodilation; Weight; Wine; base; crystalloid; drinking; epicatechin; healing; improved; in vivo; indexing; inhibitor/antagonist; interest; intravital microscopy; myocardial infarct sizing; neutrophil; polyphenol; public health relevance; red wine; research study; response; Address; Adhesions; Adhesives; Adverse effects; Alcohol consumption; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Asians; Attention; Beverages; Blood; Blood Platelets; Blood Vessels; Blood specimen; Buffers; Cardiac; Cardiovascular Diseases; Cardiovascular system; Catechin; Cells; Chocolate; Cicatrix; Cocoa Powder; Complementary and alternative medicine; Consumption; Data; Diabetes Mellitus; Disease; Dose; Eicosanoids; Endothelial Cells; Environmental Risk Factor; Epidemiology; Flavanol; Flavonoids; Flavonols; Food; Fruit; Gelatinase B; General Population; Generations; Genetic; Goals; Healed; Heart; Heart Injuries; Hispanics; Human; Incidence; Infarction; Infiltration; Inflammation; Inflammatory; Ingestion; Injury; Insulin; Insulin Resistance; Ischemia; Knockout Mice; Leukocytes; Life; Link; Longevity; Low Density Lipoprotein oxidation; Matrix Metalloproteinases; Mediating; Mediterranean Diet; Mind; Minority; Modeling; Myocardial; Myocardial Ischemia; Nitric Oxide; Nomads; Obesity; Organ; Outcome; Panama; Physical activity; Plants; Plasma; Play; Preparation; Process; Production; Proteins; Rattus; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Reporting; Risk Factors; Role; Scheme; Skeletal Muscle; Structure; Tea; Testing; Time; Tissues; Transfusion; Vasodilation; Weight; Wine; base; crystalloid; drinking; epicatechin; healing; improved; in vivo; indexing; inhibitor/antagonist; interest; intravital microscopy; myocardial infarct sizing; neutrophil; polyphenol; public health relevance; red wine; research study; response

DESCRIPTION (provided by applicant): The major objective of this proposal is to characterize the ability of cocoa and the flavanol, epicatechin, to reduce short and long-term ischemia-reperfusion induced myocardial injury in rats. Furthermore, we wish to provide evidence for the ability of cocoa and epicatechin to reduce neutrophil-mediated myocardial ischemia-reperfusion (IR) injury via a nitric oxide (NO) dependent mechanism. Polyphenols are widely distributed in plants and are known as flavonoids. Evidence indicates a negative correlation between consumption of flavonoid-rich foods and incidence of cardiovascular (CVD) disease. Cocoa powder is more than 10% flavanols (catechin and epicatechin) by weight. Interest in the beneficial effects of flavonols emerged from observations in Kuna Indians who have a very low incidence of CVD and consume minimally processed cocoa beverages. There are clues as to the mechanisms that explain cocoa effects. The consumption of flavanol rich cocoa leads to vasodilation which can be reversed by the use of an NO synthesis inhibitor. Other beneficial effects include the inhibition of platelet and leucocyte adhesion, low-density lipoprotein oxidation, reactive oxygen species (ROS) generation, eicosanoid synthesis and insulin resistance. Recent reports associate the beneficial effects of cocoa to the actions of epicatechin. The consumption of epicatechin by humans reproduces the vasodilatory effects of cocoa as well as its antioxidant and insulin sensitizing actions. Vasodilatory effects can be replicated by the use of epicatechin metabolites on isolated blood vessel preparations. Preliminary studies performed in a rat model of myocardial IR injury indicate epicatechin can exert cardioprotective effects. Treatment also reduces myocardial inflammation. Interestingly injury appears to require the presence of blood borne cells. Given the well documented beneficial effects of cocoa derived flavanols on cardiovascular parameters it is possible that these compounds may significantly reduce tissue injury and ultimately, improve long term organ structure/function. The requirement of blood to mediate tissue injury also suggests the involvement of neutrophils. With these issues in mind we propose to examine the following specific aims: Aim 1 will test the hypothesis that the administration of cocoa or epicatechin to rats leads to a reduction in myocardial IR injury and improves long term outcome. Rats will be subjected to 45 min of IR injury. Infarct size as well as myocardial injury-induced changes in cardiac structure/function will be determined up to 4 weeks post IR. ROS generation, NO production and anti-inflammatory endpoints will be determined. Studies will include the use of dose-response schemes and plasma transfusions to test for the "transferability" of protection. Aim 2 will test the hypothesis that cocoa or epicatechin treatment reduces in vivo PMN adhesion/trapping as well as their activation state. Aim 3 will test the hypothesis that cocoa or epicatechin induced increases in nitric oxide modulate (at least in part) the anti-adhesive effects of flavanols on PMN. PUBLIC HEALTH RELEVANCE: The major goal of this proposal is to characterize the ability of cocoa derived flavanols specifically epicatechin, to reduce short and long-term ischemia-reperfusion induced heart injury and to identify the role played by inflammatory cells. Given the focus on the effects of dark chocolate related flavanols we therefore address a topic relevant to the field of complementary and alternative medicine.

描述（由申请人提供）：该提案的主要目的是表征可可和黄酮醇Epicatechin的能力，以减少短期和长期缺血 - 再灌注诱导大鼠的心肌损伤。此外，我们希望提供证据证明可可和epicatechin通过一氧化氮（NO）依赖机制减少中性粒细胞介导的心肌缺血 - 再灌注（IR）损伤的能力。多酚广泛分布在植物中，被称为类黄酮。 证据表明，富含类黄酮的食物的消费与心血管疾病的发生率之间存在负相关。可可粉的重量超过10％的黄烷醇（儿茶素和表面环醇）。对于CVD发病率非常低并且食用最少加工的可可饮料的库纳印第安人的观察，对黄酮醇的有益影响的兴趣。有关于解释可可效应的机制的线索。富含黄酮醇的可可的消耗会导致血管舒张，这可以通过使用NO合成抑制剂来逆转。其他有益的作用包括抑制血小板和白细胞粘附，低密度脂蛋白氧化，活性氧（ROS）产生，eicosanoid合成和胰岛素抵抗。最近的报告将可可的有益影响与埃库辛的作用相关联。人类对epicatechin的消费再现了可可的血管舒张作用以及其抗氧化剂和胰岛素的敏感作用。血管舒张作用可以通过在分离的血管制剂上使用上表沙素代谢物来复制。在心肌损伤的大鼠模型中进行的初步研究表明，epicatechin可以发挥心脏保护作用。治疗还减少心肌炎症。 有趣的是，损伤似乎需要存在血液传播的细胞。 鉴于可可衍生的黄烷醇对心血管参数的有益作用有充分的有益作用，因此这些化合物可能会显着减少组织损伤，并最终改善长期器官的结构/功能。血液介导组织损伤的要求还表明中性粒细胞的参与。考虑到这些问题，我们建议检查以下特定目的：AIM 1将检验以下假设：可可或epicatechin对大鼠的给药会导致心肌损伤减少并改善长期结果。大鼠将遭受45分钟的IR损伤。 IR后最多4周确定梗塞大小以及心肌损伤引起的心脏结构/功能变化。将确定ROS产生，没有生产和抗炎终点。研究将包括使用剂量反应方案和血浆输血来测试保护的“可转移性”。 AIM 2将检验以下假设：可可或epicatechin治疗可降低体内PMN粘附/诱捕及其激活状态。 AIM 3将检验以下假设：可可或epicatechin诱导一氧化氮调节剂的增加（至少部分）黄酮醇对PMN的抗粘附作用。 公共卫生相关性：该提案的主要目的是表征可可衍生的黄烷醇特别是epicatechin的能力，以减少短期和长期缺血 - 再灌注诱发的心脏损伤并确定炎症细胞的作用。因此，鉴于与黑巧克力相关的黄酮的作用的关注，我们因此讨论了与互补和替代医学领域有关的主题。