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 急性心肌梗死的预后主要是由于及时的再通和更好的治疗选择 (MI)显著改善。然而，心肌梗死仍然是中国人死亡和心力衰竭的主要原因。 美国和世界各地。治疗干预在急性心肌梗死急性期是至关重要的，但也越来越多 在随后的心脏不良重塑的慢性阶段需要，这最终导致心力衰竭。 心脏病发作的幸存者越来越多。在这里，我们提出了两种新颖而不同的模式 靶向Na/K-ATP酶非酶信号转导功能的α1代表新的治疗方法 急性心脏缺血损伤后这两个疾病发展阶段的处理方法。 在急性心肌梗死急性期(目标1)，我们提出通过心脏 低浓度强心类固醇(CTS)诱导的Nka/Src受体是一种新的辅助调节 减轻经皮冠状动脉介入治疗再灌注损伤的治疗。NKA路径将是 再灌流时以FDA批准的CTS地高辛为靶点通过后处理触发保护 (PostC)，以及有或没有地高辛诱导的PostC对缺血/再灌注损伤的心肌反应将 在小鼠体内和体外进行比较。以确认地高辛PostC是通过NKA和Do 不是非靶点效应的结果，地高辛信号和对缺血再灌注的保护 心脏特异的NKAα1 KO基因工程小鼠与带有突变缺陷的补救小鼠的比较 在NKAα1/src相互作用中。 对于越来越多的能在心肌梗死中存活下来的患者，我们进一步建议有害的心脏 Nka/Src/ROS环在不良重塑中起作用，可以靶向减缓 或阻碍向心力衰竭的进展(目标2)。根据初步证据，用一种多肽进行全身治疗 设计用于在实验性急性心肌梗死预防两天后阻断NKA/Src/ROS环(PNaktie) 小鼠的不良重塑和进展为心衰。心脏特异性KO与NKA/Src相互作用 有缺陷的突变小鼠将被用来获得心脏NKA/Src信号在心脏疾病中作用的直接证据 P纳克蒂德效应。建议进行功能、组织学和生化研究，以进一步表征 随着时间的推移进行保护，并获得机械性的洞察。 鉴于导致MI(高血压、肥胖症、老龄化)的共病发病率很高且不断增加， 开发新的治疗方法以进一步提高心肌梗死后的存活率和生活质量是事关重大的。这个 拟议的研究将揭示心脏NKA/Src通路是否是一种新的、健壮的和可翻译的 信号模块在急性期和慢性期都以MI为靶点。