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.

心梗（MI）后心力衰竭（HF）是发病率和死亡率的重要原因。识别

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

Activation of EP4 receptor limits transition of acute to chronic heart failure in lipoxygenase deficient mice.

• DOI: 10.7150/thno.51183
• 发表时间: 2021
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Kain V;Ingle KA;Rajasekaran NS;Halade GV
• 通讯作者: Halade GV