MACROPHAGE HETEROGENEITY IN HEART FAILURE PROGRESSION AND CARDIAC RECOVERY

心力衰竭进展和心脏恢复中的巨噬细胞异质性

• 批准号: 10176173
• 负责人: Kory J. Lavine
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176173
• 关键词: Ablation; Acute; Adult; Aldosterone Antagonists; Angiotensin II; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Cells; Child; Childhood; Childhood Injury; Chronic; Clinical; Clinical Trials; Complex; Development; Devices; Dilated Cardiomyopathy; Disease Progression; Embryo; Gene Expression; Goals; Growth; Heart; Heart Injuries; Heart failure; Hematopoietic; Heterogeneity; Human; Immune; Inflammation; Inflammatory; Innate Immune System; Left Ventricular Function; Left Ventricular Remodeling; Mediating; Modeling; Mus; Myocardial; Neprilysin; Outcome; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Physiological; Population; Population Heterogeneity; Quality of life; Recovery; Recovery of Function; Signal Pathway; Specimen; System; Testing; Therapeutic; Tissues; Treatment Failure; Yolk Sac; angiogenesis; base; experience; experimental study; heart function; heart preservation; improved; inhibitor/antagonist; injured; innovation; ischemic cardiomyopathy; macrophage; monocyte; mortality; mouse model; neonatal injury; neonatal mice; new therapeutic target; novel; novel therapeutic intervention; progenitor; recruit; response; tissue injury; tissue repair

PROJECT SUMMARY/ABSTRACT Dilated and ischemic cardiomyopathies represent prevalent causes of heart failure and cardiovascular mortality worldwide. While landmark clinical trials have led to the establishment of effective heart failure therapies and improved clinical outcomes, mortality rates remain high and many patients ultimately experience disease progression, highlighting the clinically unmet need to identify novel treatments. Myocardial recovery is an increasingly recognized outcome for a small but significant number of patients with heart failure. Patients who experience myocardial recovery have improved quality of life and survival. Based on these observations, myocardial recovery represents an achievable outcome and a potential new therapeutic target. However, the mechanisms that dictate recovery and ultimately determine why some patients recover cardiac function while others experience disease progression are poorly defined. Remarkably, children with heart failure demonstrate a significantly greater capacity for myocardial recovery compared to adults. To dissect the mechanisms that mediate myocardial recovery in this context, we developed a mouse model of acute heart failure and successfully recapitulated the observation that the pediatric heart has a robust capacity for tissue repair and functional recovery. Mechanistically, we discovered that the injured pediatric and adult heart harbor distinct primitive and definitive macrophage subsets and that these cells govern why pediatric and adult mice display differing pathologic responses and capacities to recover following tissue injury. Collectively, these experiments uncovered a previously unrecognized complexity within the innate immune system and have challenged the paradigm that all macrophages are derived from monocyte progenitors. While these observations are thought provoking and provide proof of principle that distinct macrophage lineages have the capacity to differentially orchestrate cardiac tissue repair and heart failure progression, it is unclear how these concepts apply to the chronically failing heart. The overarching goal of this proposal is to test the hypothesis that the chronically failing mouse and human heart contains evolutionarily conserved macrophage subsets derived from distinct developmental origins that orchestrate cardiac tissue repair and adverse remodeling, respectively. Specifically, we hypothesize that primitive macrophages preserve cardiac function by stimulating tissue repair, whereas definitive monocyte-derived macrophages promote heart failure progression through inflammation, resultant collateral damage, and subsequent adverse remodeling. Clinically, the identification of reparative and inflammatory cardiac macrophage populations and elucidation of the signaling pathways by which these cells exert their effects is likely to provide the necessary information to develop novel therapeutic strategies to limit disease progression and promote recovery of the failing heart.

项目总结/摘要 扩张性和缺血性心肌病代表心力衰竭和心血管疾病的普遍原因。 全世界的死亡率。虽然具有里程碑意义的临床试验已导致建立有效的心力衰竭 治疗和改善的临床结果，死亡率仍然很高，许多患者最终经历 疾病进展，强调临床上未满足的需要，以确定新的治疗。心肌恢复是 这是一个越来越被认可的结果，用于少数但数量可观的心力衰竭患者。患者 经历心肌恢复的患者的生活质量和生存率得到改善。根据这些观察， 心肌恢复代表了可实现的结果和潜在的新治疗目标。但 决定恢复的机制，并最终决定为什么一些患者恢复心脏功能， 其他经历疾病进展的患者定义不明确。 值得注意的是，心力衰竭儿童的心肌收缩能力显着增强 与成年人相比，为了剖析在这种情况下介导心肌恢复的机制，我们 开发了一种急性心力衰竭的小鼠模型，并成功地再现了观察结果， 小儿心脏具有强大的组织修复和功能恢复能力。机械地说，我们发现 受伤的儿童和成人心脏具有不同的原始和确定的巨噬细胞亚群， 这些细胞决定了为什么儿童和成年小鼠表现出不同的病理反应和能力， 组织损伤后恢复。总的来说，这些实验揭示了一种以前未被认识到的 先天免疫系统内的复杂性，并挑战了所有巨噬细胞都是 来源于单核细胞祖细胞。虽然这些观察是发人深省的，并提供了证据， 不同的巨噬细胞谱系具有差异性协调心脏组织修复的能力的原理 和心力衰竭进展，目前尚不清楚这些概念如何适用于慢性心力衰竭。 这项提议的首要目标是检验一个假设，即慢性衰竭的小鼠和 人心脏含有进化上保守的巨噬细胞亚群，其来源于不同的发育 分别协调心脏组织修复和不良重塑的起源。我们特别 假设原始巨噬细胞通过刺激组织修复来保护心脏功能，而 永久性单核细胞衍生的巨噬细胞通过炎症促进心力衰竭进展， 附带损伤和随后的不良重塑在临床上，修复性和 炎症性心脏巨噬细胞群和阐明这些细胞 发挥其作用可能提供必要的信息，以开发新的治疗策略，以限制 疾病进展，促进衰竭心脏的恢复。

项目成果

Cardiac Lymphatic Vessels, Transport, and Healing of the Infarcted Heart.

• DOI: 10.1016/j.jacbts.2017.02.005
• 发表时间: 2017-08
• 期刊: JACC. Basic to translational science
• 作者: Huang LH;Lavine KJ;Randolph GJ
• 通讯作者: Randolph GJ

Skeletal muscle inflammation and atrophy in heart failure.

• DOI: 10.1007/s10741-016-9593-0
• 发表时间: 2017-03
• 期刊: Heart failure reviews
• 影响因子: 4.6
• 作者: Lavine KJ;Sierra OL
• 通讯作者: Sierra OL