Free fatty acid receptor 4 cardioprotective effects in cardiac ischemic injury

游离脂肪酸受体4对心脏缺血性损伤的心脏保护作用

基本信息

批准号：
10614417
负责人：
Timothy D O'Connell
金额：
$ 67.91万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614417
关键词：
Acute myocardial infarction Adult Affect Agonist Antiinflammatory Effect Attenuated Cardiac Cardiac Myocytes Cardiovascular Diseases Cell Death Chemotaxis Clinical Coronary heart disease Data Dependence Diet Disease Outcome Dose Eicosapentaenoic Acid Fatty Acids Fibroblasts Fibrosis Functional disorder G-Protein-Coupled Receptors Genes Genetic Polymorphism Heart Heart Injuries Heart failure Homeostasis Human Hypoxia Immune response In Vitro Incidence Infarction Inflammatory Ischemia Macrophage Measures Mediating Metabolic Diseases Morbidity - disease rate Mus Muscle Cells Myocardial Infarction Myocardial Ischemia Nonesterified Fatty Acids Nutrient Omega-3 Fatty Acids Outcome Pathologic Patients Phospholipase A2 Polyunsaturated Fatty Acids Production Reperfusion Injury Reperfusion Therapy Reporting Role Signal Transduction Signaling Molecule Single Nucleotide Polymorphism Supplementation Testing Therapeutic Wild Type Mouse aorta constriction cardioprotection chemokine cohort coronary fibrosis cytokine experimental study immune cell infiltrate improved improved outcome interstitial ischemic injury long chain fatty acid mortality novel offspring percutaneous coronary intervention pressure prevent receptor receptor function recruit sensor therapeutic target

项目摘要

Coronary heart disease (CHD), leading to myocardial infarction (MI) and post-MI heart failure (HF), is a major cause of morbidity and mortality in the US. w3-polyunsaturated fatty acids, like eicosapentaenoic acid (EPA), improve outcomes in CHD and HF, but this is controversial. First, several trials with low-dose w3s have failed, but recent trials with high-dose w3s (REDUCE-IT, OMEGA-REMODEL) report improved outcomes. Second, the mechanism of w3-cardioprotection is unclear, but free fatty acid receptor 4 (Ffar4), a GPCR for long-chain fatty acids, is a novel mechanism to explain w3-cardioprotection. In mice, we were the first to establish that EPA prevents cardiac fibrosis and contractile dysfunction in pressure overload. Yet, EPA was not incorporated into cardiac myocytes or fibroblasts, the traditional mechanism for EPA cardioprotection. Alternatively, we found that Ffar4 is expressed in the heart, and Ffar4 in cardiac fibroblasts in vitro was sufficient and necessary to prevent TGFb1-induced fibrosis. Thus, we hypothesized that EPA-Ffar4 signaling is necessary for EPA cardioprotection. However, we were surprised to find that Ffar4 also has w3-independent effects. In mice with systemic deletion of Ffar4 (Ffar4KO) on a standard diet, we found that TAC worsens remodeling, but without exaggerated fibrosis, highlighting the role of Ffar4 in cardiac myocytes. In myocytes, we found that Ffar4 was necessary for the expression of cardioprotective inflammatory genes and activation of phospholipase A2 (PLA2). In humans, we found that Ffar4 expression is decreased in human HF, and Ffar4 polymorphisms are associated with contractile dysfunction in Framingham Offspring. Here, we propose a novel paradigm where fatty acids function as signaling molecules to maintain cardiac homeostasis. We hypothesize that in cardiac myocytes, Ffar4 functions as an w3-independent cardioprotective, fatty acid nutrient sensor, and that Ffar4 is necessary for EPA cardioprotection. We propose four aims. 1) To determine if cardiac myocyte Ffar4 is necessary to protect against ischemia, cardiac myocyte-specific Ffar4KO mice (CM-Ffar4KO) will be subjected to ischemia-reperfusion (I/R) injury, and we hypothesize worse outcomes in the CM-Ffar4KO. 2) To define cardioprotective Ffar4 signaling mechanisms, following I/R injury in CM-Ffar4KO mice and in hypoxia in cultured myocytes, we will measure cell death, inflammatory cytokines, PLA2-induced oxylipins, and how this affects macrophage recruitment. 3) To determine if Ffar4 is necessary for EPA cardioprotection, CM-Ffar4KO on an EPA-diet will be subjected to I/R injury, and we hypothesize EPA will fail to attenuate remodeling in the CM-Ffar4KO. 4) To determine the therapeutic potential of Ffar4, wild-type mice subjected to I/R injury will treated with the Ffar4 agonist TUG-891 post-MI. In humans, we will test for associations between Ffar4 polymorphisms and CVD in clinical cohorts. Although more patients survive MI, post-MI HF is rising. Here, we propose Ffar4 as 1) a novel cardioprotective, fatty acid nutrient sensor, 2) a potential therapeutic target to attenuate post-MI remodeling, and 3) the mechanistic basis for EPA cardioprotection.

冠心病（CHD），导致心肌梗塞（MI）和MI后心力衰竭（HF）是一个美国发病和死亡率的主要原因。 w3-饱和脂肪酸，例如二糖蛋白酸（EPA），改善冠心病和HF的结果，但这是受到限制的。首先，几次低剂量w3s的试验具有失败了，但是最近对高剂量W≤3S（Reed-It，Omega-Remodel）进行的试验报告了改善的预后。其次，W≤3核保护的机理尚不清楚，但游离脂肪酸接受者4（FFAR4），GPCR的GPCR 长链脂肪酸是一种解释W3-核保护作用的新机制。在老鼠中，我们是第一个确定EPA可防止压力超负荷中的心脏纤维化和收缩功能障碍。但是，EPA不是掺入心肌细胞或成纤维细胞中，这是EPA心脏保护的传统机制。另外，我们发现FFAR4在心脏中表达，而在体外心脏成纤维细胞中的FFAR4为足以防止TGFB1诱导的纤维化。这，我们假设EPA-FFAR4信号是 EPA心脏保护所必需的。但是，我们惊讶地发现FFAR4也具有WITRIPDEPTEND 效果。在标准饮食中有系统缺失（FFAR4KO）的全身缺失的小鼠中，我们发现TAC恶化重塑，但没有夸张的纤维化，突出了FFAR4在心肌细胞中的作用。在心肌细胞中我们发现FFAR4对于表达心脏保护炎症基因和激活是必要的磷脂酶A2（PLA2）。在人类中，我们发现人类HF中的FFAR4表达降低，FFAR4 多态性与弗雷明汉后代的收缩功能障碍有关。在这里，我们提出了一本小说范围脂肪酸作为信号分子维持心脏稳态的范式。我们假设在心脏肌细胞中，FFAR4充当Wisiondiptorent的心脏保护性，脂肪酸营养传感器和该FFAR4对于EPA心脏保护是必需的。我们提出了四个目标。 1）确定是否心肌细胞 FFAR4对于预防缺血，心肌细胞特异性FFAR4KO小鼠（CM-FFAR4KO）是必要的受到缺血 - 灌注（I/R）损伤，我们假设CM-FFAR4KO的结果较差。 2）到定义心脏保护FFAR4信号传导机制，在CM-FFAR4KO小鼠中I/R损伤之后以及在缺氧中培养的肌细胞，我们将测量细胞死亡，炎性细胞因子，PLA2诱导的oxylipins，以及如何影响巨噬细胞募集。 3）确定FFAR4是否需要EPA心脏保护，CM-FFAR4KO 在EPA-DIET上将遭受I/R伤害，我们假设EPA不会减弱重塑 cm-ffar4ko。 4）确定FFAR4的治疗潜力，遭受I/R损伤的野生型小鼠将用FFAR4激动剂TUG-891在MI后处理。在人类中，我们将测试FFAR4之间的关联临床队列中的多态性和CVD。提案FFAR4 AS 1）一种新颖的心脏保护性，脂肪酸营养传感器，2）潜在的治疗靶标减弱MI后重塑，3）EPA心脏保护的机械巴西。