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.

项目摘要 主要是由于及时再灌注和更好的治疗选择，急性心肌梗塞的预后 （MI）显着改善。然而，MI仍然是死亡和心力衰竭（HF）的主要原因 美国和世界各地。在MI的急性阶段，治疗干预至关重要，但越来越多 在不良心脏重塑的随后的慢性阶段需要，最终导致HF 越来越多的心脏病生存。在这里，我们提出了两种新颖和独特的方式 靶向Na/k-ATPase（NKA）α1的非酶信号传导函数代表新治疗 急性心脏缺血性损伤后的这两个阶段中的每个阶段中的每个阶段的方法。 在MI的急性阶段（AIM 1），我们提出了通过心脏的心脏保护信号的激活 低浓度的心源类固醇（CTS）的NKA/SRC受体代表一种新型的辅助条件 经皮冠状动脉干预后减轻再灌注损伤的治疗。 NKA途径将是 以FDA批准的CTS地高辛的靶向重新灌注，以通过后调节触发保护 （Postc），以及对缺血/再灌注损伤的心肌反应，或者没有二高氧蛋白诱导的Postc 比较小鼠的体内和体内。确认地高毒素邮政信曲是通过NKA介导的，并且 不是因脱靶效应而引起的，地高辛信号传导和防止缺血 - 重新灌注的保护将是 与心脏特异性的NKAα1KO进行比较，并具有突变体有缺陷的救援 在NKAα1/SRC相互作用中。 对于越来越多的MI生存的患者，我们进一步提出了有害的心脏 NKA/SRC/活性氧（ROS）环在重塑中起作用，可以靶向缓慢 或钝化到HF（AIM 2）。基于初步证据，用肽进行全身治疗 旨在阻止NKA/SRC/ROS环（PNAKTIDE）在实验急性MI防止后两天 不良重塑和向小鼠中HF的进展。心脏特异性KO和NKA/SRC相互作用 有缺陷的突变小鼠将用于获得心脏NKA/SRC信号的作用的直接证据 pnaktide效应。提出了功能，组织学和生化研究，以进一步表征 随着时间的推移保护并获得机械洞察力。 考虑到导致MI（高血压，肥胖，衰老）的合并症患病率较高且增加 在开发新型疗法方面，赌注很高，以进一步提高MI后的生存率和生活质量。这 拟议的研究应显而易见的是心脏NKA/SRC途径是否是一种新颖，健壮且可翻译的 在MI的急性相和慢性相中，信号模块靶向靶向。