Unconventional IL-1 signaling in heart failure

心力衰竭中的非常规 IL-1 信号传导

• 批准号: 10560648
• 负责人: Antonio Abbate
• 金额: $ 0.7万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-20 至 2023-02-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10560648
• 关键词: Adaptor Signaling Protein; Apical; Binding; Cardiac; Cardiac Myocytes; Cardiomyopathies; Clinical Research; Coronary; Data; Development; Diagnosis; Disease; Disease Marker; Dissociation; Dizziness; Dose; Dyspnea; Elderly; Epidemic; Exposure to; Fatigue; Frequencies; Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genetic; Heart; Heart failure; Hospitalization; Hour; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-1 Receptors; Interruption; Ischemia; Knockout Mice; Knowledge; Ligation; Link; Malignant Neoplasms; Measures; Mediating; Mediator; Modeling; Mus; Myeloid Cells; Myocardial dysfunction; Myocardial tissue; NF-kappa B; Operative Surgical Procedures; Output; PDE 3B; PIK3CG gene; Pathway interactions; Patients; Phosphatidylinositols; Phosphotransferases; Play; Population; Predisposition; Prevalence; Prognosis; Property; Protein Isoforms; Proteins; Quality of life; Receptor Signaling; Role; Signal Transduction; Small Interfering RNA; Symptoms; System; Testing; Time; anakinra; beta-adrenergic receptor; chemokine receptor; cofactor; cost; cytokine; desensitization; epidemiologic data; heart function; hospital readmission; improved; in vivo; inhibitor; mRNA Expression; mortality; mouse model; novel therapeutic intervention; novel therapeutics; pharmacologic; preclinical study; preservation; pressure; prevent; protein expression; reduce symptoms; scaffold; systemic inflammatory response

Heart failure (HF) represents a final common pathway for both ischemic and non-ischemic cardiomyopathy, with an annual incidence >600,000 new cases each year, a disease prevalence >6 million patients, and an estimated annual cost >$30 billion in the USA alone. Improved understanding of HF pathophysiology throughout recent decades has led to critical advances in HF prognosis through neurohormonal blockade. Despite these improvements, the HF mortality rate remains extraordinarily high (>30% within 5 years of diagnosis) and HF remains the leading cause for hospitalization in patients >65 years (a growing segment of the US population). The HF epidemiologic data suggest that the current treatment paradigm fails to interrupt one or more key pathophysiologic mechanisms of HF, and confirm the urgent need to develop novel therapeutic approaches to alleviate symptoms of HF, improve quality of life, and reduce re-hospitalization for HF. The evidence supporting the presence of inflammation in HF is overwhelming. One of the unanswered questions is whether inflammation plays a key role in the progression of HF or is merely a marker of disease. Recent data from our group and others have shown that the systemic inflammatory response in patients with HF can be inhibited with the use of a targeted Interleukin-1 (IL-1) blockers, anakinra or canakinumab. Both in preclinical and clinical studies, in parallel with reducing systemic inflammation, IL-1 blockers preserved or restored cardiac function, whether the effects on systemic inflammation and on cardiac function are intertwined and cannot be dissociated, or whether they are independent has not been explored. IL-1 is a master regulator of the inflammatory response, namely NF-kB activation, that is shared with many other cytokines and is part of the redundancy of the system. An unconventional signaling of the IL-1 receptor signaling through the phosphoinositide-3 kinase γ (PI3Kγ) has been characterized in inflammation and cancer. Whether IL-1 signaling in HF is mediated through PI3Kγ remains unknown. We hypothesize that enhanced levels of IL-1 increase PI3K p110γ expression in cardiomyocytes, that in turn results in selective induction of p87 co- signaling, and cardiac dysfunction through a scaffolding function on PDE3B. To test this hypothesis, we will determine whether IL-1 induces p110γ and p87 in cardiomyocytes in vitro and in vivo (Aim #1); whether PI3Kγ mediates IL-1 induced systolic dysfunction in vivo (Aim #2); and whether we can distinguish the kinase- dependent from the scaffolding function of PI3Kγ in cardiac dysfunction (Aim #3). Determining the mechanisms by which inflammation, and IL-1 in specific, contributes to cardiac dysfunction may open the way to more and better ways to prevent and treat heart failure – which is an urgent unmet need.

心力衰竭（HF）代表了缺血性和非缺血性心肌病的最终共同途径，每年的发病率> 60万例新病例，疾病患病率> 600万患者，仅在美国，估计每年的年费用> 300亿美元。在最近几十年中，人们对HF病理生理学的了解得以提高，从而通过神经激素阻断导致了HF预后的关键进展。尽管有这些改善，但HF死亡率仍然非常高（在诊断后5年内> 30％），而HF仍然是> 65岁的患者住院的主要原因（美国人口的越来越多）。 HF流行病学数据表明，当前的治疗范例未能中断HF的一种或多种关键的病理生理机制，并确认迫切需要开发新的治疗方法来减轻HF症状，改善生活质量，并减少HF的重新携带者。支持HF炎症存在的证据是压倒性的。未解决的问题之一是炎症在HF的发展中是否起关键作用，还是仅仅是疾病的标志。我们小组和其他人的最新数据表明，使用靶向白介素-1（IL-1）阻滞剂，anakinra或cankinumab的HF患者的全身性炎症反应可以抑制。在临床前和临床研究中，与减少全身感染的同时，IL-1阻滞剂保留或恢复心脏功能，无论对全身感染和对心脏功能的影响相互交织并且无法解离，还是尚未探索它们。 IL-1是炎症反应的主要调节剂，即NF-KB激活，它与许多其他细胞因子共享，并且是系统冗余的一部分。 IL-1接收器信号通过磷酸肌醇3激酶γ（PI3Kγ）的非常规信号传导已在炎症和癌症中表征。 HF中的IL-1信号是否是通过PI3Kγ介导的，仍然未知。我们假设IL-1的水平增强了心肌细胞中PI3Kp110γ的表达，这又导致通过PDE3B上的脚手架功能选择性地诱导p87共同信号和心脏功能障碍。为了检验这一假设，我们将确定IL-1是否在体内诱导收缩功能障碍（AIM＃2）；以及我们是否可以将激酶依赖性与心脏功能障碍中PI3Kγ的脚手架功能区分开（AIM＃3）。确定炎症和特异性炎症和IL-1的机制有助于心脏功能障碍，这可能为预防和治疗心力衰竭的更多更好的方法开辟了道路 - 这是紧迫的未满足需求。