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

Na/K-ATP酶受体作为心肌梗死的新型治疗靶点

• 批准号: 9813314
• 负责人: Sandrine V Pierre
• 金额: $ 44.4万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-10 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813314
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Accounting; Acute; Acute myocardial infarction; Address; Aging; Biochemical; Cardiac; Cardiac Glycosides; Cardiac Myocytes; Cause of Death; Cessation of life; Chronic; Chronic Phase; Communication; Comorbidity; Complex; Developed Countries; Development; Digoxin; Disease Progression; Dose; FDA approved; Generations; Genetically Engineered Mouse; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Histologic; Hypertension; Injections; Injury; Institutes; Interdisciplinary Study; Ion Transport; Ischemia; Lead; Ligands; Mediating; Medical; Mentors; Modality; Modeling; Morphology; Mus; Mutant Strains Mice; Myocardial; Myocardial Infarction; Myocardial dysfunction; Na(+)-K(+)-Exchanging ATPase; Obesity; Pathway interactions; Patients; Peptides; Pharmacology; Phase; Physiology; Play; Prevalence; Protein Kinase C; Quality of life; Reactive Oxygen Species; Records; Reperfusion Injury; Reperfusion Therapy; Research; Role; Secondary to; Signal Pathway; Signal Transduction; Structure; Survival Rate; Survivors; Testing; Therapeutic; Therapeutic Intervention; Time; United States; Universities; Validation; base; cardioprotection; conditioning; design; disability; drug candidate; heart preservation; improved; in vivo; insight; mortality; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; percutaneous coronary intervention; polypeptide; preconditioning; prevent; programs; receptor; receptor function; response; src-Family Kinases; tool; undergraduate student

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.

项目概要 急性心肌梗死的预后主要归功于及时的再灌注和更好的治疗选择 然而，MI 仍然是死亡和心力衰竭 (HF) 的主要原因。 在美国和世界各地，治疗干预在心肌梗死的急性期至关重要，而且也越来越重要。 在随后的不良心脏重塑慢性阶段中需要，最终导致心力衰竭 在此，我们提出两种新颖且独特的治疗方式。 靶向 Na/K-ATPase (NKA) α1 的非酶信号传导功能代表了新的治疗方法 急性心脏缺血性损伤后疾病进展的这两个阶段的方法。 在 MI 的急性期（目标 1），我们建议通过心脏功能激活心脏保护信号 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理 减轻经皮冠状动脉介入治疗再灌注损伤的治疗将是NKA途径。 以 FDA 批准的 CTS 地高辛为目标，在再灌注时通过后处理触发保护 (PostC)，无论有或没有地高辛诱导的 PostC，心肌对缺血/再灌注损伤的反应都会 在小鼠体内进行离体和体内比较，以确认地高辛 PostC 是通过 NKA 介导的。 地高辛信号传导和缺血再灌注保护不是由脱靶效应引起的 与心脏特异性 NKA α1 KO 基因工程小鼠进行比较，并用突变缺陷进行拯救 NKA α1/Src 相互作用。 对于越来越多的心肌梗死患者来说，我们进一步建议，有害的心脏疾病 NKA/Src/活性氧 (ROS) 环在不良重塑中发挥作用，可以有针对性地减缓 或减缓心力衰竭的进展（目标 2）。 设计用于在实验性急性心肌梗塞两天后阻断 NKA/Src/ROS 循环 (pNaktide) 小鼠心脏特异性 KO 和 NKA/Src 相互作用的不良重塑和进展。 有缺陷的突变小鼠将用于获得心脏 NKA/Src 信号传导在 提出了功能、组织学和生化研究来进一步表征 pNaktide 效应。 随着时间的推移提供保护并获得机械洞察力。 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， 开发新疗法以进一步提高心肌梗死后的生存率和生活质量至关重要。 拟议的研究将揭示心脏 NKA/Src 通路是否是一种新颖、稳健且可转化的通路 信号模块针对 MI 的急性期和慢性期。