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

摘要 急性缺血性损伤，如心肌梗死(MI)，是导致 心力衰竭(HF)是一种进行性疾病，影响着数百万患者，每年造成数十亿美元的损失。 白细胞在缺血损伤后迅速招募到心脏，在那里它们调节各种不同的 反应包括心肌细胞存活、纤维化、梗死稳定和血运重建。最初， 炎性和吞噬白细胞被招募来降解死亡细胞和受损的基质，其次是 修复性白细胞，稳定心肌，解决损伤。因此，对余额的调制 缺血损伤后心脏内白细胞依赖性炎症和消退过程之间的关系 最近努力减少长期的不利的缺血后重塑和持续性 与慢性心力衰竭相关的炎症。交感神经系统可以影响白细胞 过程，部分通过刺激β-肾上腺素能受体(βAR)信号，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 造血细胞(β2ARKO BMT小鼠)在心肌梗死后心脏破裂中表现出100%的死亡率， 这与心脏中白细胞募集减少有关。从机械上讲，我们有 证明β-2AR以信号通路偏向的方式调节白细胞对心脏的反应 损伤通过G蛋白偶联受体激酶(Grk)/β-arrestin(βARR)依赖的β2AR信号传导。产生于 这项工作是关于β2AR信号在多大程度上调节炎症和修复的问题 心脏损伤后的白细胞数量及其存活率，以及偏向的β-2AR信号是否提供了 调节这些过程以改善心脏重塑结果的新方法。此外，由于β2AR 缺失对白细胞功能有负面调节作用，临床使用的β阻滞剂有可能 同样影响白细胞对缺血损伤的反应性和受损心肌内的存活率。 因此，我们的目标是：1)确定急性白血病后白细胞存活中β-2AR表达依赖的变化。 2)评价β阻滞剂治疗对小鼠和人白细胞功能的影响 3)白细胞特异性偏向的β-2AR信号在心脏重构和心脏重构中的作用 受伤后的存活。总体而言，我们将从根本上了解这些机制和影响 研究β-2AR信号在心脏损伤早期免疫反应中的作用及确定β-2AR是否具有选择性 治疗学将提供微调策略来调节缺血损伤诱导的重塑和生存 结果。

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.