Mechanisms of Lipotoxic Arrhythmias

脂毒性心律失常的机制

基本信息

批准号：
10119665
负责人：
Ademuyiwa Aromolaran
金额：
$ 43.75万
依托单位：
MASONIC MEDICAL RESEARCH LABORATORY, INC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10119665
关键词：
2&apos -adenylic acid Acid Phosphatase Action Potentials Adenosine Monophosphate Adult Age Animal Disease Models Arrhythmia Atrial Fibrillation Cardiac Cavia Cell surface Cells Chronic Data Dependence Deposition Development Diet Disease Down-Regulation Dyslipidemias Electric Stimulation Epidemic Ethers Exhibits Fat-Restricted Diet Fatty acid glycerol esters Functional disorder Gene Expression Genes Genetic Goals Heart Heart Atrium High Fat Diet Human Hyperglycemia Hyperlipidemia Impairment Incidence Inflammation Injections Intervention Ion Channel Link Lipids Maintenance Measurement Measures Mental Depression Methodology Modeling Molecular Mus Muscle Cells Myocardium Nonesterified Fatty Acids Obesity Obesity Epidemic Oleic Acids Optics Overweight Palmitic Acids Pathogenesis Pathologic Pathway interactions Patients Pharmacology Phosphatidylinositide 3-Kinase Inhibitor Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Population Post-Translational Protein Processing Potassium Channel Predisposition Prevention Protein Dephosphorylation Protein Kinase Protein Overexpression Protein Serine/Threonine Phosphatase Protein phosphatase Protocols documentation Public Health Publishing Regulation Risk Role Serum Signal Pathway Surface Surface Properties Tachycardia Testing Therapeutic Effect Time Treatment Efficacy Up-Regulation Work base density design effective therapy extracellular gene therapy heart cell innovation insight mortality new therapeutic target novel palmitoylation predictive marker prevent protein kinase inhibitor receptor response targeted treatment therapeutic evaluation tool trafficking voltage

项目摘要

Project Summary/Abstract: High-fat diet induced lipotoxicity is an epidemic that poses a significant public health problem with over one-third of the world population being either overweight or obese, and is associated with arrhythmias. While lipotoxicity has been linked to atrial fibrillation (AF) in patients and in animal disease models, little is known about the underlying molecular pathways for dysregulation. We propose that a critical contributor to lipotoxic atrial disease involves pathological dysregulation of the delayed rectifier K current IK composed of the rapidly (IKr) and slowly activating (IKs) components, both of which are critical for cardiac repolarization. In ventricles, pathological decreases in pore-forming subunits of IKr (hERG) and IKs (KCNQ1) have been linked by our group and others to arrythmogenic IKr and IKs currents. We recently discovered for the first time that IK currents are upregulated in obese guinea pigs atria contribute prominently to enhanced action potential repolarization. We also found that palmitic acid abbreviated action potential duration and increased IKr and IKs densities; while oleic acid prolonged action potential duration, and severely reduced IKr but had no effect on IKs. Our new preliminary data indicate that these guinea pigs exhibit lipotoxicity with no signs of hyperglycemia or inflammation. Furthermore, intracardiac injection of palmitic acid increased IK density and vulnerability to spontaneous atrial arrhythmias in guinea pigs as early as 5 weeks of age. We now propose to use this unique model to more comprehensively define the molecular mechanisms of arrhythmogenesis, to explore whether altered functional expression of IKr and IKs contributes to the pathogenesis and maintenance of AF, and whether targeting altered IK channel function could be an effective treatment for AF. Three specific aims are proposed: Aim 1: To examine the downstream pathways by which lipotoxicity increases IK channel function. We will test, using genetic and pharmacological approaches, whether increased IKr and IKs functional expression is involved in the remodeling of the myocardium in response to lipotoxicity and whether activators of AMPK and inhibitors of PI3K downstream pathways can normalize IK channel functional expression. Aim 2: To test the causal link between increased IK and susceptibility to AF in lipotoxic heart. We will utilize genetic and pharmacological interventions to see whether IK plays a role in AF and whether it may be a novel therapeutic target. Aim 3: To test therapeutically the causal link between PP2A activation, selective downregulation of IKr and prevention of AF in lipotoxicity. The proposed studies may identify important links between dysfunctional IKr and IKs channels, defective lipid-dependent signaling pathways in AF, and protein kinase-phosphatase dysfunction. Our proposed comprehensive studies are designed to provide rigorous and robust hypothesis driven testing to reveal new understandings of the molecular basis of AF. By establishing AMPK/PI3K/PP2A or downstream targets as predictive markers of AF, our data may inform the development of novel, mechanism-based effective treatment options.

项目摘要/摘要：高脂肪饮食引起的脂毒性是一种流行病，造成了超过三分之一的严重公共卫生问题世界人口超重或肥胖，并与心律失常有关。同时具有脂毒性在患者和动物疾病模型中，它与心房颤动（AF）有关，但人们对它知之甚少。失调的潜在分子途径。我们认为脂毒性心房疾病的一个关键因素涉及延迟整流器 K 电流 IK 的病理性失调，该电流由快速电流 (IKr) 和缓慢电流组成激活（IK）成分，这两者对于心脏复极都至关重要。在心室中，病理性我们的小组和其他人将 IKr (hERG) 和 IKs (KCNQ1) 成孔亚基的减少与致心律失常 IKr 和 IKs 电流。我们最近首次发现 IK 电流在肥胖豚鼠心房对增强动作电位复极化有显着贡献。我们还发现棕榈酸缩短动作电位持续时间并增加 IKr 和 IK 密度；而油酸则延长动作电位持续时间，并严重降低 IKr，但对 IK 没有影响。我们的新初步数据表明这些豚鼠表现出脂毒性，但没有高血糖或炎症的迹象。此外，心脏内注射棕榈酸会增加 IK 密度并增加自发性房性心律失常的易感性豚鼠 5 周大时。我们现在建议使用这种独特的模型来更全面地定义心律失常发生的分子机制，探讨 IKr 功能表达是否改变和 IK 有助于 AF 的发病机制和维持，以及靶向是否改变了 IK 通道功能可能是 AF 的有效治疗方法。提出了三个具体目标：目标 1：审查脂毒性增加 IK 通道功能的下游途径。我们将使用遗传和药理学方法，增加 IKr 和 IKs 功能表达是否参与重塑心肌对脂毒性的反应以及 AMPK 激活剂和 PI3K 抑制剂是否下游通路可以使 IK 通道功能表达正常化。目标 2：测试之间的因果关系脂毒性心脏中的 IK 和 AF 易感性增加。我们将利用遗传和药物干预看看 IK 是否在 AF 中发挥作用以及它是否可能是一个新的治疗靶点。目标 3：测试 PP2A 激活、IKr 选择性下调和 AF 预防之间的治疗因果关系脂毒性。拟议的研究可能会确定功能失调的 IKr 和 IKs 通道之间的重要联系， AF 中脂质依赖性信号通路有缺陷，以及蛋白激酶磷酸酶功能障碍。我们提出的全面的研究旨在提供严格而稳健的假设驱动测试，以揭示新的了解 AF 的分子基础。通过建立 AMPK/PI3K/PP2A 或下游目标作为 AF 的预测标志物，我们的数据可能为开发基于机制的新型有效治疗方法提供信息选项。