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Mechanisms of Lipotoxic Arrhythmias

脂毒性心律失常的机制

基本信息

批准号：
10487956
负责人：
Ademuyiwa Aromolaran
金额：
$ 38.38万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-11 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10487956
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 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 diet-induced obesity dietary 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：高脂饮食引起的脂毒性是一种流行病，它构成了一个重大的公共健康问题，超过三分之一世界人口中有一半超重或肥胖，并与心律失常有关。而脂肪毒性在患者和动物疾病模型中与心房颤动(AF)有关，但对其知之甚少调节失调的潜在分子途径。我们认为脂中毒性心房疾病的一个关键因素涉及由快速(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，这两个成分都对心脏复极至关重要。在脑室，病理性的 Ikr(Herg)和Iks(KCNQ1)成孔亚基的减少已经被我们的小组和其他人联系到致心律失常的Ikr和Iks流。我们最近首次发现，Ik电流在肥胖的豚鼠心房对动作电位复极的增强有显著贡献。我们还发现，棕榈酸缩短动作电位时程，增加Ikr和Iks密度，而油酸则延长动作电位时程，并严重降低Ikr，但对Iks无影响。我们新的初步数据显示这些豚鼠表现出脂肪毒性，没有高血糖或炎症的迹象。此外，心内注射棕榈酸可增加自发性房性心律失常的易感性豚鼠最早只有5周大。我们现在建议使用这一独特的模式来更全面地明确心律失常发生的分子机制，探讨IKR功能表达的改变 IKs参与了房颤的发生和维持，以及是否靶向改变了的IK通道功能可能是治疗房颤的有效方法。提出了三个具体目标：目标1：审查脂肪毒性增加IK通道功能的下游途径。我们将进行测试，使用基因和药理学方法：IKR和IKS功能表达增加是否参与重塑以及AMPK激活剂和PI3K抑制剂是否下游通路可使IK通道功能表达正常化。目标2：测试两者之间的因果关系脂毒性心脏的IK增加，房颤易感性增加。我们将利用遗传和药物干预为了了解IK是否在房颤中起作用，以及它是否可能成为一个新的治疗靶点。目标3：测试 PP2A激活、IKR选择性下调与预防房颤的因果关系脂肪毒性。所提出的研究可以识别功能失调的IKR和IKS通道之间的重要联系，房颤中脂质依赖信号通路的缺陷，以及蛋白激酶-磷酸酶功能障碍。我们的建议全面的研究旨在提供严格和稳健的假设驱动测试，以揭示新的对房颤分子基础的认识。通过将AMPK/PI3K/PP2A或下游目标建立为房颤的预测标记物，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择。