Adenosine Signaling During Post-Infarction Remodeling and Heart Failure

梗死后重塑和心力衰竭期间的腺苷信号转导

• 批准号: 9317191
• 负责人: JOHN A AUCHAMPACH
• 金额: $ 44.77万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317191
• 关键词: ADORA2B gene; Activation Analysis; Acute myocardial infarction; Address; Adenosine; Adenosine A2B Receptor; American; Biological Assay; Biology; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Survival; Cells; Chronic; Chronic lung disease; Cicatrix; Clinical; Coronary Arteriosclerosis; Coronary artery; Coupled; Data; Disease; Excision; Experimental Animal Model; Exposure to; Family; Fibroblasts; Fibrosis; Functional disorder; G alpha q Protein; Gene Targeting; Genetic; Genets; Heart; Heart failure; Infarction; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Kidney; Kidney Diseases; Kinetics; Ligation; Link; Liver; Liver diseases; Lung; Macrophage Activation; Mediator of activation protein; Microdialysis; Modeling; Molecular Analysis; Mus; Muscle; Myelogenous; Myocardial Infarction; Myocardial Ischemia; Myocardium; Organ; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmacology; Pharmacotherapy; Population; Process; Production; Purinergic P1 Receptors; Rattus; Recurrence; Research Project Grants; Role; Signal Transduction; Skin; Son; Survival Rate; Symptoms; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Work; adenosine deaminase; base; blood pump; cytokine; experience; extracellular; healing; improved; injured; interstitial; macrophage; member; mouse model; mutant; new therapeutic target; novel; novel therapeutics; prevent; repaired; response; skin disorder; tissue repair

ABSTRACT The interstitial concentration of adenosine remains elevated following MI continuing well after the injured tissue has healed and a scar has formed. However, the impact of adenosine signaling during post-MI remodeling and chronic ischemic heart failure remains unknown. In other organs, the novel concept has emerged that adenosine becomes damaging if it remains persistently elevated in tissues by activating pathways that promote fibrosis. This has been observed in experimental animal models of chronic lung, liver, kidney, and skin diseas- es. While the mechanisms by which adenosine becomes damaging vary, it generally acts to promote exces- sive tissue repair via activation of the A2BAR. The A2BAR is a unique member of the AR family abundantly ex- pressed in macrophages linked to cellular activation and production of inflammatory/fibrogenic cytokines. To determine the contribution of adenosine signaling during post-MI remodeling, we examined the effect of genet- ic deletion or blockade of the A2BAR (ATL-801) in a mouse model of permanent coronary artery ligation. Our preliminary data show a marked reduction in fibrosis with loss of A2BAR signaling at 8 weeks post-MI, which was associated with reduced inflammatory/fibrogenic activity in heart tissue, less dysfunction, and improved compliance. Central hypothesis: Augmented production of adenosine persists following MI, which contributes to fibrosis, pathological remodeling, and heart failure via activation of the A2BAR subtype. Aim #1 will define the role of A2BAR signaling during post-MI remodeling. We will test whether genetic deletion or inhibition of the A2BAR will slow the rate of fibrosis that develops in surviving myocardium following MI resulting in less dysfunc- tion and ultimately prolonged survival. This aim will be accomplished using ATL-801, Adora2b-/- mice, as well as a new line of Adora2b mutant rats created by our lab. Aim #2: To delineate the mechanisms by which A2BAR signaling contributes to adverse post-MI remodeling. Utilizing a conditionally targeted mouse line lack- ing expression of the A2BAR in myeloid-derived cells, assessments of macrophage infiltration/activation, and molecular analyses of post-MI heart tissue, we will test the hypothesis that persistent exposure to adenosine following MI stimulates the production of inflammatory mediators from macrophages that causes chronic in- flammation, fibroblast activation, and fibrosis. Aim #3: To delineate the magnitude and consequences of en- hanced adenosine production during post-MI remodeling and ischemic heart failure. We will assess changes in the interstitial concentration of adenosine in the surviving myocardium during the course of post-MI remodel- ing. We hypothesize that the interstitial concentration of adenosine will increase progressively during late re- modeling as the heart fails and that its enzymatic removal with pegylated-adenosine deaminase therapy will be protective. Completion of this work is expected to identify adenosine as an important fibrogenic mediator in the heart that contributes to pathological remodeling following MI through its interaction with the A2BAR subtype, and potentially identify a novel target for therapeutic intervention for patients with ischemic heart disease.

摘要 心肌梗死后，腺苷的间质浓度在损伤组织后仍保持升高 已经愈合了，形成了一个伤疤然而，腺苷信号在心肌梗死后重构中的影响 慢性缺血性心力衰竭仍不清楚。在其他机构，出现了一个新的概念， 如果腺苷在组织中持续升高，它会激活促进细胞增殖的途径， 纤维化这已经在慢性肺、肝、肾和皮肤疾病的实验动物模型中观察到- es.虽然腺苷成为破坏性的机制各不相同，但它通常会促进过量的腺苷酸。 通过激活A2 BAR进行主动组织修复。A2 BAR是AR家族的独特成员， 在与细胞活化和炎症/纤维化细胞因子产生相关的巨噬细胞中被挤压。到 为了确定腺苷信号在心肌梗死后重构中的作用，我们检测了基因的作用， 在永久性冠状动脉结扎的小鼠模型中A2 BAR（ATL-801）的ic缺失或阻断。我们 初步数据显示，心肌梗死后8周，随着A2 BAR信号的丢失， 与心脏组织中炎症/纤维化活性降低、功能障碍减少和改善相关 合规中心假设：心肌梗死后腺苷的产生持续增加， 通过激活A2 BAR亚型导致纤维化、病理性重塑和心力衰竭。目标#1将定义 A2 BAR信号在心肌梗死后重构中的作用我们将测试是否基因缺失或抑制， A2 BAR将减缓MI后存活心肌中纤维化的发展速度，从而减少功能障碍。 最终延长生存期。该目的也将使用ATL-801、Adora 2b-/-小鼠来实现 我们实验室培育的Adora 2b突变鼠目标#2：描述 A2 BAR信号传导有助于不利的MI后重构。利用一个有条件的目标鼠标线缺乏- A2 BAR在骨髓源性细胞中的表达，巨噬细胞浸润/活化的评估，和 通过对MI后心脏组织的分子分析，我们将检验持续暴露于腺苷的假设 MI后刺激巨噬细胞产生炎症介质，导致慢性炎症， 炎症、成纤维细胞活化和纤维化。目的#3：描述的程度和后果的en- 在心肌梗死后重塑和缺血性心力衰竭期间增加腺苷的产生。我们将评估变化 心肌梗死后重塑过程中存活心肌中腺苷的间质浓度- ing.我们推测，在晚期再灌注过程中，间质腺苷浓度将逐渐增加。 模型的心脏衰竭，其酶清除与聚乙二醇化腺苷脱氨酶治疗将是 保护性的这项工作的完成，预计将确定腺苷作为一个重要的纤维化介质，在 心肌梗死后通过与A2 BAR亚型相互作用导致病理性重塑的心脏， 并可能为缺血性心脏病患者的治疗干预确定新的靶点。