The Na/K-ATPase receptor function as a novel therapeutic target in myocardial infarction

项目摘要 由于及时的再灌注和更好的治疗选择，急性心肌梗死的预后 (MI)有了显著的改善。然而，MI仍然是心脏病患者死亡和心力衰竭（HF）的主要原因。 美国和世界各地。治疗性干预在心肌梗死急性期至关重要，但也越来越多地 需要在随后的慢性期不良心脏重塑，最终导致HF中， 越来越多的心脏病幸存者在这里，我们提出两种新颖而独特的模式， 靶向Na/K-ATP酶（NKA）α1的非酶信号传导功能代表了新的治疗方法， 在急性心脏缺血性损伤后疾病进展的这两个阶段中的每一个中的方法。 在MI的急性期（目的1），我们提出通过心脏保护信号的激活， 低浓度强心类固醇（CTS）的NKA/Src受体代表了一种新型的辅助调节 治疗以减轻经皮冠状动脉介入治疗后的再灌注损伤。NKA途径将是 在再灌注时用FDA批准的CTS地高辛靶向，通过后处理触发保护作用 （PostC），以及心肌对缺血/再灌注损伤的反应，有或没有地高辛诱导的PostC将 在小鼠中进行离体和体内比较。确认地高辛PostC通过NKA介导， 不是脱靶效应的结果，地高辛信号传导和对缺血-再灌注的保护将是 在心脏特异性NKA α1 KO的基因工程小鼠和突变缺陷型NKA α1 KO的拯救小鼠中进行比较， NKA α1/Src相互作用。 对于越来越多的心肌梗死患者，我们进一步提出， NKA/Src/活性氧（ROS）环在不良重塑中起作用，可以靶向减缓 或减缓向HF的进展（目标2）。根据初步证据，用肽进行全身治疗 设计用于在实验性急性MI后两天阻断NKA/Src/ROS环（pNaktide）， 在小鼠中的不良重塑和进展为HF。心脏特异性KO和NKA/Src相互作用 缺陷突变小鼠将被用于获得心脏NKA/Src信号传导在心肌细胞凋亡中作用的直接证据。 pNaktide效应。功能，组织学和生物化学研究提出进一步表征， 保护随着时间的推移，并获得机械的见解。 鉴于导致MI的合并症（高血压、肥胖、衰老）的患病率较高且不断增加， 开发新的治疗方法以进一步提高MI后的生存率和生活质量的风险很高。的 拟议的研究将揭示心脏NKA/Src通路是否是一种新的、稳健的和可翻译的 在MI的急性期和慢性期两者中靶向信号传导模块。

Project Summary Owing mostly to timely reperfusion and better treatment options, the prognosis of acute myocardial infarction (MI) has significantly improved. Nevertheless, MI remains a major cause of death and heart failure (HF) in the US and around the world. Therapeutic intervention is critical in the acute phase of MI, but also increasingly needed in the subsequent chronic phase of adverse cardiac remodeling, which ultimately leads to HF in the growing number of survivors of a heart attack. Here, we propose that two novel and distinct modalities targeting the non-enzymatic signaling function of Na/K-ATPase (NKA) α1 represent novel therapeutic approaches in each of these two phases of disease progression following an acute cardiac ischemic injury. In the acute phase of MI (Aim 1), we propose that activation of cardioprotective signaling through the cardiac NKA/Src receptor by low concentrations of cardiotonic steroids (CTS) represents a novel adjunct conditioning treatment to mitigate reperfusion injury upon percutaneous coronary intervention. The NKA pathway will be targeted with the FDA-approved CTS digoxin at reperfusion to trigger protection through postconditioning (PostC), and myocardial response to ischemia/reperfusion injury with or without digoxin-induced PostC will be compared ex vivo and in vivo in mice. To confirm that digoxin PostC is mediated through NKA and does not result from an off-target effect, digoxin signaling and protection against ischemia-reperfusion will be compared in genetically engineered mice with cardiac-specific NKA α1 KO and rescue with a mutant defective in NKA α1/Src interaction. For the increasing number of patients who will survive MI, we further propose that a deleterious cardiac NKA/Src/reactive oxygen species (ROS) loop plays a role in adverse remodeling and can be targeted to slow or blunt the progression to HF (Aim 2). Based on preliminary evidence, systemic treatment with a peptide designed to block the NKA/Src/ROS loop (pNaktide) two days after an experimental acute MI prevents adverse remodeling and progression to HF in the mouse. Cardiac-specific KO and NKA/Src interaction defective mutant mice will be used to obtain direct evidence of the role of cardiac NKA/Src signaling in the pNaktide effect. Functional, histological, and biochemical studies are proposed to further characterize the protection over time and obtain mechanistic insight. Given the high and increasing prevalence of co-morbidities leading to MI (hypertension, obesity, aging), the stakes are high in developing novel therapies to further improve survival rates and quality of life after MI. The proposed studies shall reveal whether the cardiac NKA/Src pathway is a novel, robust and translatable signaling module to target in both the acute phase and chronic phase of MI.