Unconventional IL-1 signaling in heart failure

心力衰竭（HF）代表缺血性和非缺血性心肌病的最终共同途径，仅在美国，每年新发病例> 600，000例，疾病患病率> 600万患者，估计年成本> 300亿美元。近几十年来，对HF病理生理学的理解不断加深，通过神经激素阻滞在HF预后方面取得了重大进展。尽管有这些改善，HF死亡率仍然非常高（诊断后5年内>30%），HF仍然是>65岁患者（美国人口的增长部分）住院的主要原因。HF流行病学数据表明，目前的治疗模式未能中断HF的一个或多个关键病理生理机制，并证实迫切需要开发新的治疗方法来缓解HF症状，改善生活质量，减少HF再住院。支持HF中存在炎症的证据是压倒性的。其中一个未回答的问题是炎症是否在HF的进展中起关键作用，或者仅仅是疾病的标志物。来自我们小组和其他人的最新数据表明，HF患者的全身炎症反应可以通过使用靶向白细胞介素-1（IL-1）阻断剂，阿那白滞素或卡那单抗来抑制。在临床前和临床研究中，与减少全身炎症平行，IL-1阻滞剂保留或恢复心脏功能，对全身炎症和对心脏功能的影响是否相互交织且不能分离，或者它们是否是独立的尚未探索。IL-1是炎症反应（即NF-κ B活化）的主要调节剂，其与许多其他细胞因子共享，并且是系统冗余的一部分。通过磷酸肌醇-3激酶γ（PI 3 K γ）的IL-1受体信号传导的非常规信号传导已在炎症和癌症中表征。HF中的IL-1信号传导是否通过PI 3 K γ介导仍不清楚。我们假设IL-1水平的提高增加了心肌细胞中PI 3 K p110γ的表达，这反过来导致选择性诱导p87共信号传导，并通过PDE 3B上的支架功能导致心功能障碍。为了检验这一假设，我们将确定IL-1是否在体外和体内诱导心肌细胞中的p110γ和p87（目标#1）; PI 3 K γ是否在体内介导IL-1诱导的收缩功能障碍（目标#2）;以及我们是否可以区分心脏功能障碍中PI 3 K γ的激酶依赖性功能和支架功能（目标#3）。确定炎症，特别是IL-1导致心功能不全的机制可能会为预防和治疗心力衰竭开辟更多更好的方法-这是一个迫切的未满足的需求。

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.