Unconventional IL-1 Signaling in Heart failure

心力衰竭（HF）是缺血性和非缺血性心肌病的最终共同途径，每年新发病例60万例，疾病患病率600万例，仅在美国估计每年花费300亿美元。近几十年来，对心衰病理生理学的理解不断提高，导致了通过神经激素阻断治疗心衰预后的关键进展。尽管有这些改善，心衰的死亡率仍然非常高（诊断后5年内达到30%），心衰仍然是65岁以上（美国人口中越来越多的一部分）患者住院的主要原因。心衰流行病学数据表明，目前的治疗模式未能中断心衰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心衰症状，改善生活质量，减少心衰再次住院。支持心衰患者存在炎症的证据是压倒性的。一个悬而未决的问题是炎症是否在HF的进展中起关键作用，或者仅仅是疾病的一个标志。我们小组和其他研究人员最近的数据表明，使用靶向白介素-1 （IL-1）阻滞剂anakinra或canakinumab可以抑制HF患者的全身炎症反应。在临床前和临床研究中，IL-1受体阻滞剂在减轻全身炎症的同时，保留或恢复了心功能，对全身炎症的影响与对心功能的影响是否相互交织、不可分离，或者两者是否相互独立，尚未得到探讨。IL-1是炎症反应的主要调节因子，即NF-kB激活，它与许多其他细胞因子共享，是系统冗余的一部分。IL-1受体通过磷酸肌醇-3激酶γ (PI3Kγ)的非常规信号传导已在炎症和癌症中被表征。HF中的IL-1信号是否通过PI3Kγ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PI3K p110γ的表达，进而导致p87共信号的选择性诱导，并通过PDE3B的支架功能导致心功能障碍。为了验证这一假设，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 (Aim #1)；PI3Kγ是否介导IL-1诱导的体内收缩功能障碍（Aim #2）；以及我们能否区分PI3Kγ在心功能障碍中的激酶依赖性和支架功能（Aim #3）。确定炎症，特别是IL-1导致心功能障碍的机制，可能会为预防和治疗心力衰竭开辟更多更好的途径——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.