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：高脂饮食引起的脂肪毒性是一种流行病，构成了一个重大的公共卫生问题，其中三分之一以上在世界人口中，人口超重或肥胖，与心律不齐有关。而脂肪毒性与患者和动物疾病模型中的心房颤动（AF）有关，对此知之甚少基础分子途径用于失调。我们建议造成脂肪毒性心房疾病的关键因素涉及延迟整流器k电流IK的病理失调，并慢慢组成激活（IK）成分，这两种成分对于心脏复极化至关重要。在心室中，病理学 IKR（HERG）和IKS（KCNQ1）的孔形成亚基的减小已被我们的小组和其他人联系在一起 Arrythmogenic IKR和IKS电流。我们最近首次发现IK电流上调肥胖的几内亚猪心房对增强的动作潜在的重极化作出了重要贡献。我们还发现棕榈酸缩写的作用潜在持续时间，并增加了IKR和IKS密度；而油酸延长动作潜在的持续时间，并严重减少了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肪毒性，没有高血糖或炎症的迹象。此外，心脏内注射棕榈酸增加了IK的密度和自发性心律不齐的脆弱性豚鼠早在5周龄时。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，以探索IKR的功能表达是否改变 IK和IK有助于AF的发病机理和维持，以及靶向IK通道是否改变功能可能是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通道函数的下游途径。我们将使用遗传和药理学方法，IKR和IKS功能表达是否涉及重塑响应脂肪毒性以及AMPK激活剂和PI3K抑制剂的心肌的响应下游途径可以使IK通道功能表达式标准化。目标2：测试之间的因果关系 IK和对脂肪毒性心脏AF的易感性提高。我们将利用遗传和药理干预措施看看IK是否在AF中扮演角色以及它是否可能是新型的治疗靶点。目标3：测试从治疗上，PP2A激活，IKR的选择性下调和预防AF之间的因果关系脂肪毒性。拟议的研究可能会确定功能失调的IKR和IKS渠道之间的重要联系， AF中的脂质依赖性信号通路和蛋白激酶 - 磷酸酶功能障碍的缺陷。我们提出的综合研究旨在提供严格而强大的假设驱动测试，以揭示新的对AF的分子基础的理解。通过建立AMPK/PI3K/PP2A或下游目标作为 AF的预测标记，我们的数据可能会为基于机制的新型有效治疗的发展提供信息选项。