Mechanisms of Lipotoxic Arrhythmias

脂毒性心律失常的机制

• 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
• 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' -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

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.

项目概要/摘要： 高脂饮食引起的脂毒性是一种流行病，造成了一个重大的公共卫生问题，超过三分之一的 超重或肥胖的世界人口中，并与心律失常有关。虽然脂毒性 在患者和动物疾病模型中， 导致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 包括由快速（IKr）和缓慢（IKr）组成的延迟整流钾电流IK的病理性失调 激活（IKs）成分，这两者对心脏复极化至关重要。心室中，病理性 我们的研究小组和其他人已经将IKr（hERG）和IKs（KCNQ 1）的成孔亚基减少与 引起心律失常的IKr和IKs电流。我们最近首次发现，IK电流上调， 肥胖豚鼠心房显著地促进了动作电位复极的增强。我们还发现 棕榈酸缩短动作电位时程，增加IKr和IKs密度，油酸延长动作电位时程， 动作电位持续时间，并严重降低IKr，但对IKs没有影响。我们新的初步数据显示 这些豚鼠表现出脂毒性，没有高血糖或炎症的迹象。此外，委员会认为， 心内注射棕榈酸可增加IK密度和对自发性房性心律失常的易感性 豚鼠早在5周龄时。我们现在建议使用这种独特的模式， 明确肿瘤发生的分子机制，探讨IKr的功能表达是否改变， 和IKs有助于AF的发病机制和维持，以及是否靶向改变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：检查 脂毒性增加IK通道功能的下游途径。我们将测试，使用基因和 药理学方法，增加IKr和IKs功能表达是否参与重塑 以及AMPK激活剂和PI 3 K抑制剂 下游通路可使IK通道功能表达正常化。目标2：检验下列因素之间的因果关系： 脂毒性心脏IK增加和AF易感性增加。我们将利用遗传和药物干预 以了解IK是否在AF中发挥作用以及它是否可能成为新的治疗靶点。目标3：测试 在治疗上，PP 2A激活、IKr选择性下调和AF预防之间存在因果关系。 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中的脂质依赖性信号通路缺陷和蛋白激酶-磷酸酶功能障碍。我们提出的 全面的研究旨在提供严格和强大的假设驱动测试，以揭示新的 通过建立AMPK/PI 3 K/PP 2A或下游靶点， 作为房颤的预测标志物，我们的数据可能会为开发新的、基于机制的有效治疗提供信息 选项.