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常见途径，仅在美国每年就有60万新病例发生，600万患者患病，估计每年花费300亿美元。近几十年来，对心力衰竭病理生理学的认识不断提高，通过神经激素的阻断，使得心力衰竭预后的研究取得了重大进展。尽管有这些改进，心力衰竭的死亡率仍然非常高(确诊后5年内为30%)，心力衰竭仍然是65岁患者住院的主要原因(在美国人口中，这是一个不断增长的部分)。心力衰竭的流行病学数据表明，目前的治疗模式未能阻断心力衰竭的一个或多个关键的病理生理机制，并证实迫切需要开发新的治疗方法来缓解心力衰竭的症状，提高生活质量，减少心力衰竭的再住院。支持心力衰竭存在炎症的证据是压倒性的。其中一个悬而未决的问题是，炎症是在心力衰竭的发展过程中发挥关键作用，还是仅仅是疾病的一个标志。来自我们小组和其他人的最新数据表明，使用靶向白细胞介素1(IL-1)阻滞剂anakinra或canakinumab可以抑制心力衰竭患者的全身炎症反应。在临床前和临床研究中，在减轻全身炎症的同时，IL-1受体阻滞剂在保留或恢复心功能的同时，对全身炎症和心功能的影响是相互交织而不能分离的，还是相互独立的，尚未被探索。IL-1是炎症反应即核因子-kB激活的主要调节因子，与许多其他细胞因子共享，是系统冗余的一部分。IL-1受体通过磷脂酰肌醇-3激酶γ(PI3Kγ)的非常规信号转导已在炎症和癌症中得到了表征。目前尚不清楚心衰时IL-1信号是否通过PI3Kγ介导。我们假设，IL-1水平的升高增加了心肌细胞中PI3K p110γ的表达，进而导致选择性地诱导p87共信号，并通过对PDE3B的支架功能而导致心功能障碍。为了验证这一假说，我们将确定IL-1是否在体外和体内诱导心肌细胞p110γ和p87(目标1)；PI3Kγ是否在体内介导IL-1诱导的收缩功能障碍(目标2)；以及我们是否能在心功能障碍中区分PI3Kγ的激酶依赖和支架功能(目标3)。确定炎症，特别是IL-1导致心脏功能障碍的机制，可能会为预防和治疗心力衰竭开辟更多和更好的方法--这是一种迫切的未得到满足的需求。

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.