Resolution of Inflammation in Heart Failure Post-Myocardial Infarction

心肌梗塞后心力衰竭炎症的消退

• 批准号: 10085520
• 负责人: Ganesh V Halade
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10085520
• 关键词: Acute; Adult; American; American Heart Association; Antibodies; Binding; Blood; CD59 Antigen; Cell physiology; Cells; Characteristics; Chronic; Clinical; Computer Models; Congestive Heart Failure; Data; Disease; Docosahexaenoic Acids; Economic Burden; Emigrations; Event; FPR2 gene; Fibroblasts; Fibrosis; Flow Cytometry; Foundations; Goals; Heart; Heart failure; Human; ITGAM gene; Immune; Immune signaling; In Vitro; Inflammation; Inflammatory; Investigation; Knockout Mice; Lead; Left Ventricular Remodeling; Left ventricular structure; Leukocytes; Ligands; Link; Lipids; Lipoxins; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Medical; Minor; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardium; Myofibroblast; Neprilysin; Neutrophil Activation; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Outcome; Pathway interactions; Patients; Peptides; Phase; Phenotype; Population; Process; Resolution; Role; Scheme; Signal Transduction; Spleen; Structure; T-Lymphocyte; Testing; Therapeutic; Time; Translations; Work; base; cytokine; effective therapy; healing; heart damage; heart function; improved; in silico; in vivo; indexing; innovation; lipid mediator; macrophage; monocyte; mortality; neutrophil; novel; outcome forecast; prevent; receptor; screening; statistics; therapeutic target; trafficking; treatment strategy; wound healing

Heart failure (HF) after myocardial infarction (MI) is a significant cause of morbidity and mortality. Identifying the events that limit adverse remodeling of the left ventricle (LV) post-MI will provide therapeutic targets to prevent, slow, or reverse progression to HF. MI initiates the “get-in” signal for immune cells including neutrophils, which if unchecked causes uncontrolled pro-inflammatory activity that in turn leads to HF. Our post-MI studies suggest that spleen coordinates the resolution of inflammation through a cardiosplenic pathway. These findings reveal an urgent clinical need to establish the mechanisms by which the spleen mediates this resolution. It was previously believed that resolution of inflammation is an inert process, but emerging data confirms that this is an active process managed by specialized pro-resolving molecules (SPMs) derived from omega-3 and omega-6 fatty acids. Our R00 study in an HF setting confirms that the spleen produces various SPMs, including lipoxins, resolvins, and maresins post-MI, and exogenous treatment with resolvin D1 (RvD1) clears inflammation in a cardiosplenic manner. We discovered that exogenous RvD1 clears neutrophils and resolves inflammation by activating neutrophil-expressed formyl peptide receptor 2 (FPR2) in the left ventricle and spleen post-MI. This proof-of-concept study using RvD1 in mice provides the foundation for investigation of the resolvins-mediated mechanism of action in chronic HF. These data implicate activation of neutrophil receptors in promoting the “get-out” signal for effective resolution of inflammation post-MI. To achieve our overall goal of activating immune cells in the healing phase after MI, we propose to establish: 1) the role of RvD1 in resolution of inflammation in chronic HF; 2) whether activation of this “get-out” signal is enough to resolve post-MI inflammation in HF using FPR2 knockout mice to abolish RvD1 action and resultant HF; and 3) the novel mechanism of action of RvD1 on neutrophil-expressed CD10 in the cardiosplenic axis, as suggested by our innovative in silico computational modeling. Our initial studies in mice have confirmed the role of RvD1 in acute HF. Now, we propose a mechanistic study to extend in silico, ex vivo, and acute HF (day 5) outcomes to chronic HF (day 28), which is key for translation and to indicate survival benefit to HF patients. Non-immunosuppressive pro-resolving therapy is an unmet medical need and has the potential to be the first ever effective therapy to control chronic inflammation and delay HF in a cardiosplenic manner. These studies will identify immune cell-specific novel targets for lipid mediators in a ligand-receptor-specific pathway, rather than antibody or cytokine-specific inhibition, which will likely enhance therapeutic applications in patients with HF within the next 5-6 years.

心肌梗塞（MI）后心力衰竭（HF）是发病率和死亡率的重要原因。识别 限制左心室（LV）MI的广告重塑的事件将为治疗目标提供 预防，缓慢或反向向HF。 MI启动了免疫细胞的“加入”信号，包括 中性粒细胞，如果未检查会引起不受控制的促炎活性，从而导致HF。我们的 MI后的研究表明，脾脏通过心铂协调炎症的分辨率 路径。这些发现表明，紧急临床需要建立sleen的机制 调解该决议。以前认为解决炎症是一个惰性过程，但是 新兴数据证实，这是一个由专门的促分子分子（SPM）管理的主动过程 源自Omega-3和Omega-6脂肪酸。我们在HF环境中的R00研究证实了SLEEN 在MI后产生各种SPM，包括Lipoxins，Resolvins和Maresins，以及外源治疗 Resolvin D1（RVD1）以心脾脏方式清除注射。我们发现外源RVD1清除 嗜中性粒细胞并通过激活嗜中性粒细胞表达的甲基肽受体2（FPR2）中的炎症。 左心室和脾脏后。这项使用RVD1在小鼠中使用RVD1的概念证明为基础提供了基础 用于ResolveVins介导的作用机理的投资。这些数据暗示激活 中性粒细胞受体在促进“脱离”信号中以有效解决MI后的炎症。到 在MI之后，在愈合阶段激活免疫细胞的总体目标，我们建议建立：1） RVD1在慢性HF中炎症解决方案中的作用； 2）激活此“脱离”信号是否是 足够使用FPR2基因敲除小鼠在HF中解析MI后注射以消除RVD1动作和结果 HF; 3）RVD1对嗜中性粒细胞表达的CD10的新型作用机理，AS 由我们在计算机计算建模中创新的建议。我们在小鼠中的最初研究证实了 RVD1在急性HF中的作用。现在，我们提出了一项机械研究，以延伸到硅，离体和急性HF（天 5）慢性HF的结果（第28天），这是翻译的关键，表明对HF患者的生存益处。 非免疫抑制性促分解疗法是一种未满足的医疗需求，有可能成为第一个 每种有效的疗法，以心脾脏方式控制慢性注射和延迟HF。这些研究 将确定在配体特异性途径中脂质介质的免疫细胞特异性新靶 而不是抗体或细胞因子特异性抑制，这可能会增强 HF在未来5 - 6年内。

项目成果

Obesity and Cardiometabolic Defects in Heart Failure Pathology.

• DOI: 10.1002/cphy.c170011
• 发表时间: 2017-09-12
• 期刊: Comprehensive Physiology
• 影响因子: 5.8
• 作者: Halade GV;Kain V
• 通讯作者: Kain V

Metabolic and Biochemical Stressors in Diabetic Cardiomyopathy.

• DOI: 10.3389/fcvm.2017.00031
• 发表时间: 2017
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Kain V;Halade GV
• 通讯作者: Halade GV

Immune responsive resolvin D1 programs peritoneal macrophages and cardiac fibroblast phenotypes in diversified metabolic microenvironment.

• DOI: 10.1002/jcp.27165
• 发表时间: 2019-04
• 期刊: Journal of cellular physiology
• 影响因子: 5.6
• 作者: Kain V;Halade GV
• 通讯作者: Halade GV

Dysfunction of resolution receptor triggers cardiomyopathy of obesity and signs of non-resolving inflammation in heart failure.

• DOI: 10.1016/j.mce.2021.111521
• 发表时间: 2022-02-15
• 期刊: MOLECULAR AND CELLULAR ENDOCRINOLOGY
• 影响因子: 4.1
• 作者: Kain, Vasundhara;Halade, Ganesh, V
• 通讯作者: Halade, Ganesh, V

Novel biomarkers of inflammation in heart failure with preserved ejection fraction: analysis from a large prospective cohort study.

• DOI: 10.1186/s12872-022-02656-z
• 发表时间: 2022-05-14
• 期刊: BMC cardiovascular disorders
• 影响因子: 2.1