Beta adrenergic receptor-dependent regulation of leukocytes in acute cardiac injury

急性心脏损伤中白细胞的β肾上腺素受体依赖性调节

• 批准号: 10063903
• 负责人: Douglas Tilley
• 金额: $ 39.63万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063903
• 关键词: Acute; Address; Affect; Bone Marrow; Bone Marrow Transplantation; Cardiac; Cardiac Myocytes; Cell Survival; Cells; Chronic; Clinical; Congestive Heart Failure; Coupled; Data; Down-Regulation; Equilibrium; Fibrosis; G protein coupled receptor kinase; GTP-Binding Proteins; Goals; Heart; Heart Injuries; Heart failure; Hematopoietic; Human; Hypertrophy; Immune; Immune response; Infarction; Inflammation; Inflammatory; Injury; Knock-out; Leukocytes; Mus; Myocardial; Myocardial Infarction; Myocardial rupture; Myocardium; Outcome; Pathway interactions; Patients; Peptide Hydrolases; Phagocytes; Phosphotransferases; Play; Population; Process; Progressive Disease; Proteins; Publishing; Receptor Signaling; Regulation; Reporting; Resolution; Role; Sampling; Signal Pathway; Signal Transduction; Sympathetic Nervous System; Testing; Therapeutic; Work; beta-2 Adrenergic Receptors; beta-adrenergic receptor; beta-arrestin; cardiac repair; cardiogenesis; cell injury; chemokine receptor; cost; cytokine; improved; injured; interest; ischemic injury; macrophage; monocyte; mortality; mouse model; neutrophil; novel strategies; receptor; recruit; response; survival outcome; therapeutic target; transcriptome

Summary Acute ischemic injury, such as myocardial infarction (MI), is a major contributor toward the development of heart failure (HF), a progressive disease affecting millions of patients and costing billions of dollars annually. Leukocytes are rapidly recruited to the heart after ischemic injury where they regulate a wide variety of responses including cardiomyocyte survival, fibrosis, infarct stabilization and revascularization. Initially, inflammatory and phagocytic leukocytes are recruited to degrade dead cells and damaged matrix, followed by reparative leukocytes to stabilize the myocardium and resolve the injury. As such, modulation of the balance between leukocyte-dependent inflammation and resolution processes within the heart after ischemic injury is at the forefront of recent efforts to diminish prolonged adverse post-ischemic remodeling and persistent inflammation associated with chronic HF. The sympathetic nervous system can influence leukocyte processes, in part via stimulation of β-adrenergic receptor (βAR) signaling, and becomes activated after cardiac injury. We recently showed that, compared to normal mice, chimeric mice lacking β2AR expression in cells of hematopoietic origin (β2ARKO BMT mice) displayed 100% mortality via cardiac rupture following MI, which was associated with decreased leukocyte recruitment to the heart. Mechanistically, we have demonstrated that β2AR acts in a signaling pathway-biased manner to regulate leukocyte responses to cardiac injury via G protein coupled receptor kinase (GRK)/β-arrestin (βarr)-dependent β2AR signaling. Arising from this work are questions related to the extent to which β2AR signaling regulates inflammatory versus reparative leukocyte populations and their survival following cardiac injury, and whether biased β2AR signaling offers a novel approach to regulate these processes to improve cardiac remodeling outcomes. Further, since β2AR deletion negatively regulates leukocyte functions, the possibility exists that clinically used β-blockers may similarly impact leukocyte responsiveness to ischemic injury and survival within the injured myocardium. Therefore, we aim to 1) define the β2AR expression-dependent alterations in leukocyte survival following acute cardiac injury, 2) evaluate the impact of β-blocker treatment on mouse and human leukocyte function and survival, and 3) differentiate the effects of leukocyte-specific biased β2AR signaling on cardiac remodeling and survival following injury. Overall, we will attain a fundamental understanding of the mechanisms and influence of β2AR signaling on the early immune response to cardiac injury and determine whether β2AR-selective therapeutics would offer fine-tuned strategies to regulate ischemic injury-induced remodeling and survival outcomes.

总结 急性缺血性损伤，如心肌梗死（MI），是导致心肌梗死的主要因素。 心力衰竭（HF），一种影响数百万患者并且每年花费数十亿美元的进行性疾病。 白细胞在缺血性损伤后迅速募集到心脏，在那里它们调节各种各样的细胞因子。 结果表明，心肌细胞存活、纤维化、梗死稳定化和血管再生是心肌细胞存活的主要原因。起初， 募集炎性和吞噬性白细胞以降解死细胞和受损基质， 修复性白细胞以稳定心肌并解决损伤。因此，平衡的调节 白细胞依赖性炎症和缺血性损伤后心脏内的消退过程之间的关系， 最前沿的最近的努力，以减少长期不利的缺血后重塑和持续 与慢性HF相关的炎症。交感神经系统可影响白细胞 过程，部分通过刺激β-肾上腺素能受体（βAR）信号传导，并在 心脏损伤我们最近发现，与正常小鼠相比，缺乏β2AR表达的嵌合小鼠在小鼠中的表达水平明显降低。 造血来源的细胞（β2ARKO BMT小鼠）显示出100%的死亡率， 这与心脏白细胞募集减少有关。机械地说，我们有 表明β 2 AR以信号通路偏向的方式调节白细胞对心脏的反应， 通过G蛋白偶联受体激酶（GRK）/β-抑制蛋白（β-arrestin，β 2 AR）依赖性信号传导的损伤。产生 这项工作是关于β2AR信号调节炎症与修复的程度的问题。 白细胞数量及其在心脏损伤后的存活率，以及偏性β2AR信号是否提供了一个 调节这些过程以改善心脏重塑结果的新方法。此外，由于β2AR 缺失负调节白细胞功能，临床使用的β受体阻滞剂可能 类似地影响白细胞对缺血性损伤的反应性和损伤心肌内的存活。 因此，我们的目标是：1）确定急性脑梗死后白细胞存活中β 2 AR表达依赖性的改变， 心脏损伤，2）评价β-受体阻滞剂治疗对小鼠和人白细胞功能的影响， 存活，和3）区分白细胞特异性偏向β 2 AR信号传导对心脏重塑的影响， 受伤后的生存。总的来说，我们将从根本上了解这些机制和影响， 研究β 2 AR信号对心脏损伤早期免疫应答的影响，并确定β 2 AR选择性 治疗将提供微调策略来调节缺血性损伤诱导的重塑和存活 结果。