Eicosapentaenoic acid activation of free fatty acid receptor 4 prevents fibrosis, microvascular rarefaction, and diastolic dysfunction; implications for heart failure preserved ejection fraction

二十碳五烯酸激活游离脂肪酸受体 4，可预防纤维化、微血管稀疏和舒张功能障碍；

• 批准号: 9175471
• 负责人: Timothy D O'Connell
• 金额: $ 38.42万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-22 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175471
• 关键词: Affect; Atherosclerosis; Atrial Fibrillation; Blood; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; Clinical Trials; Complex; Coronary heart disease; Data; Dependency; Diagnosis; Diet; Dose; EFRAC; Eicosapentaenoic Acid; Endothelial Cells; Erythrocytes; Extracellular Matrix; Failure; Fatty Acids; Fibroblasts; Fibrosis; Functional disorder; G-Protein-Coupled Receptors; General Population; Heart; Heart failure; Human; Hypertrophy; Incidence; Inflammation; Ischemia; Knockout Mice; Left; Left Ventricular Hypertrophy; Left Ventricular Remodeling; Ligands; Limb structure; Measures; Mediating; Membrane; Meta-Analysis; Modeling; Myofibroblast; Natriuretic Peptides; Nonesterified Fatty Acids; Omega-3 Fatty Acids; Outcome; Oxygen; Pathologic; Patients; Plasma; Polyunsaturated Fatty Acids; Prevention; Production; Reporting; Risk Reduction; Sudden Death; Symptoms; Syndrome; Testing; Therapeutic; Therapeutic Index; Time; Vascular Endothelial Growth Factors; Ventricular; angiogenesis; base; chronotropic; clinical efficacy; cohort; constriction; exercise intolerance; improved; improved outcome; in vivo; indexing; interstitial; long chain fatty acid; mouse model; novel; novel therapeutics; prevent; receptor; uptake

Over half of all heart failure (HF) diagnoses are HF with preserved ejection fraction (HFpEF), a complex syndrome defined by symptoms of HF but a `normal' left ventricular EF. HFpEF is characterized by diastolic dysfunction, impaired filling, hypertrophy, and elevated natriuretic peptides. Presently, there are no treatments that improve survival in patients with HFpEF. Pathologic remodeling in HFpEF includes interstitial fibrosis and microvascular rarefaction, which contribute to diastolic stiffness, impaired ventricular filling, and exercise intolerance. Fibrosis results from activation of fibroblasts leading to increased extracellular matrix production, fibroblast proliferation, and fibroblast-to-myofibroblast transformation. Microvascular rarefaction is associated with inflammation and endothelial cell death, leading to impaired oxygen delivery, reducing systolic and diastolic reserve, and exacerbating exercise intolerance. We found that ω3-polyunsaturated fatty acids (ω3- PUFA) inhibited myofibroblast transformation and prevented interstitial fibrosis and diastolic dysfunction in a mouse model that partially resembles HFpEF (transverse aortic constriction, TAC). Further, we found that blood levels of eicosapentaenoic acid (EPA) correlated with prevention of interstitial fibrosis, but EPA was not incorporated into fibroblast membranes in vivo, a traditional mechanism of action. Rather, we found that free fatty acid receptor 4 (FFAR4), a G-protein coupled receptor for long-chain fatty acids, was sufficient and required to prevent myofibroblast transformation in cardiac fibroblasts. Other groups reported that ω3-PUFAs induce angiogenesis in hind-limb ischemia, and EPA activates FFAR4 to induce VEGF-A expression. Thus, EPA might have a dual benefit in HFpEF by preventing fibrosis and microvascular rarefaction. In humans, ω3- PUFAs reduce sudden death in coronary heart disease, but questions of efficacy remain. However, failure to achieve adequate ω3-PUFA levels, or a therapeutic index, likely explains prior negative results. Thus, we hypothesize that sufficient dietary uptake of EPA (therapeutic level) and activation of FFAR4 prevents fibrosis, microvascular rarefaction, and diastolic dysfunction in HFpEF. To test this we will: 1) Determine if erythrocyte EPA concentration (EPA-index) correlates with prevention of fibrosis, microvascular rarefaction, and diastolic dysfunction following TAC. We will also target FFAR4 with cpdA, a novel FFAR4 ligand, as a potential therapeutic approach to reverse remodeling following TAC. 2) Determine if high plasma levels of EPA prevent progression of left ventricular hypertrophy and fibrosis as well as HFpEF in humans using data from the Multi- Ethnic Study of Atherosclerosis trial (MESA). 3) Use fibroblast-specific FFAR4 knockout mice to determine if FFAR4 is required for EPA mediated prevention of fibrosis, microvascular rarefaction, and diastolic dysfunction following TAC. The impact will be to: 1) Identify novel cardioprotective functions of EPA, 2) Define a therapeutic index for EPA-mediated cardioprotection, 3) Provide evidence for the clinical efficacy of EPA/ FFAR4 to prevent HFpEF, and 4) Delineate a novel mechanism of action for EPA, activation of FFAR4.

超过一半的心力衰竭（HF）诊断为HF，保留了射血分数（HFPEF），这是一个复杂的 由HF的符号定义的综合征，但是“正常”左心室EF。 HFPEF的特征是舒张期 功能障碍，填充受损，肥大和脂肪胡椒粉升高。目前，没有治疗 这可以改善HFPEF患者的生存。 HFPEF中的病理重塑包括间质纤维化和 微血管罕见，有助于舒张期僵硬，心室填充障碍和运动 intlerance。纤维化是由成纤维细胞激活导致细胞外基质产生增加的引起的， 成纤维细胞增殖和成纤维细胞对肌纤维细胞的转化。微血管稀疏与 炎症和内皮细胞死亡，导致氧递送受损，减少收缩期和 舒张期储备和加剧运动摄入率。我们发现ω3-饱和脂肪酸（ω3- PUFA）抑制肌纤维细胞的转化，并防止间质纤维化和舒张功能障碍 部分类似于HFPEF的鼠标模型（横向主动脉收缩，TAC）。此外，我们发现 eicosapentaenoic酸（EPA）的血液水平与预防间质纤维化相关，但EPA不是 在体内掺入成纤维细胞膜中，这是一种传统的作用机理。相反，我们发现这是免费的 脂肪酸受体4（FFAR4）是一种用于长链脂肪酸的G蛋白偶联受体，足够，并且 防止心脏成纤维细胞中的肌纤维细胞转化所需。其他小组报告说ω3-PUFA 诱导Hind-LIMB缺血中的血管生成，EPA激活FFAR4以诱导VEGF-A表达。那， EPA通过预防纤维化和微血管稀有性可以在HFPEF中具有双重好处。在人类中，ω3- PUFA减少了冠心病的猝死，但仍然存在效率问题。但是，无法 达到足够的ω3-PUFA水平或治疗指数，可能会解释先前的负面结果。那，我们 假设EPA的足够饮食摄取（治疗水平）和FFAR4的激活可防止纤维化， HFPEF中的微血管罕见和舒张功能障碍。为了测试这一点，我们将：1）确定是否红细胞 EPA浓度（EPA索引）与预防纤维化，微血管稀疏和舒张期有关 TAC后功能障碍。我们还将用一种新型的FFAR4配体CPDA靶向FFAR4，作为潜力 TAC后逆转重塑的治疗方法。 2）确定EPA高血浆水平是否防止 左心室肥大和纤维化的进展以及人类中HFPEF的进展，使用来自多数的数据 动脉粥样硬化试验（MESA）的种族研究。 3）使用成纤维细胞特异性的FFAR4基因敲除小鼠确定是否是否 FFAR4是EPA介导的预防纤维化，微血管罕见和舒张功能障碍所必需的 跟随TAC。影响将是：1）确定EPA的新型心脏保护功能，2）定义A EPA介导的心脏保护的治疗指数，3）提供了EPA/临床效率的证据 FFAR4预防HFPEF，4）描绘了EPA的新型作用机理，即FFAR4的激活。