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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：
10386829
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/10386829
关键词：
Acute myocardial infarction Adult Affect Agonist Antiinflammatory Effect Attenuated Cardiac Cardiac Myocytes Cardiovascular Diseases Cell Death Cells Chemotaxis Clinical Coronary heart disease Data Dependence Diet Disease Outcome Dose Eicosapentaenoic Acid Fatty Acids Fibroblasts Fibrosis Functional disorder G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Gene Activation Genes Genetic Polymorphism Heart Heart Injuries Heart failure Homeostasis Human Hypoxia Immune Immune response In Vitro Incidence Infarction Infiltration Inflammatory Ischemia Measures Mediating Metabolic Diseases Morbidity - disease rate Mus Muscle Cells Myocardial Infarction Nonesterified Fatty Acids Nutrient Omega-3 Fatty Acids Outcome Pathologic Patients Phospholipase A2 Polyunsaturated Fatty Acids Production Reperfusion Injury Reperfusion Therapy Reporting Role Signal Induction Signal Transduction Signaling Molecule Single Nucleotide Polymorphism Supplementation Testing Therapeutic Wild Type Mouse cardioprotection chemokine cohort constriction coronary fibrosis cytokine experimental study improved improved outcome interstitial ischemic injury long chain fatty acid macrophage 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）是一种常见的心血管疾病，可导致心肌梗死（MI）和心肌梗死后心力衰竭（HF）。在美国发病率和死亡率的主要原因。ω 3-ω多不饱和脂肪酸，如二十碳五烯酸 (EPA)，改善CHD和HF的预后，但这是有争议的。失败了，但最近的试验与高剂量的wm 3s（REDUCE-REMODEL，欧米茄-REMODEL）报告改善的结果。第二，wf 3-kD心脏保护的机制尚不清楚，但游离脂肪酸受体4（Ffar 4），一种GPCR，长链脂肪酸，是一种新的机制来解释wt 3-β心肌保护作用。在小鼠中，我们是第一个证实EPA可预防压力超负荷时心脏纤维化和收缩功能障碍。然而， EPA的心脏保护作用的传统机制是将EPA掺入心肌细胞或成纤维细胞。另外，我们发现Ffar 4在心脏中表达，并且在体外心脏成纤维细胞中Ffar 4被表达。因此，我们假设EPA-TGF β 1-far 4信号通路是一种重要的信号通路，然而，我们惊讶地发现，Ffar 4也具有不依赖于wP 3-ATP的功能。在标准饮食的Ffar 4系统性缺失（Ffar 4KO）小鼠中，我们发现TAC抑制了Ffar 4的表达。重构，但没有过度的纤维化，突出了Ffar 4在心肌细胞中的作用。在肌细胞中，我们发现，Ffar 4对于心脏保护性炎症基因的表达和激活在人中，我们发现Ffar 4表达在人HF中降低，并且Ffar 4表达在人HF中降低。多态性与心脏收缩功能障碍有关。在这里，我们提出了一种新的脂肪酸作为信号分子维持心脏稳态的范式。我们假设在心肌细胞中，Ffar 4作为一种不依赖于wt 3的心脏保护性脂肪酸营养传感器发挥作用， Ffar 4是EPA心脏保护所必需的，我们提出了四个目标：1）确定心肌细胞是否 Ffar 4是保护免于缺血所必需的，将心肌细胞特异性Ffar 4KO小鼠（CM-Ffar 4KO）缺血再灌注（I/R）损伤，我们假设CM-Ffar 4KO的结果更糟。在CM-Ffar 4基因敲除小鼠I/R损伤后和缺氧条件下，培养的心肌细胞，我们将测量细胞死亡，炎症细胞因子，磷脂酶A2-β诱导的氧化脂质，以及这是如何发生的。 3）为了确定Ffar 4是否是EPA心脏保护所必需的，CM-Ffar 4KO 将受到I/R损伤，我们假设EPA将无法减弱I/R中的重塑。 4）为了确定Ffar 4的治疗潜力，将经历I/R损伤的野生型小鼠在人类中，我们将测试Ffar 4与TUG-891之间的关联。尽管更多的患者在心肌梗死后存活，但心肌梗死后HF的发生率正在上升。提出Ffar 4作为1）一种新的心脏保护性脂肪酸营养传感器，2）一种潜在的治疗靶点，减弱心肌梗死后重构，和3）EPA心脏保护的机制基础。