Transcriptional Regulation of Ion Channels in Heart Failure and Arrhythmias

心力衰竭和心律失常中离子通道的转录调节

• 批准号: 10084059
• 负责人: Isabelle Deschenes
• 金额: $ 59.96万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084059
• 关键词: Transcriptional; Regulation; Ion; Channels; Heart

 DESCRIPTION (provided by applicant): Cardiac arrhythmias are a leading cause of morbidity and mortality within developed nations. Often, these arrhythmias are associated with acquired heart diseases, notably cardiac heart failure (HF), where the dysregulation of a host of ion transporters and channels is observed. Particularly, a critical imbalance of both depolarizing INa and repolarizing Ito is observed. Our previous work was the first to support the nascent idea that expression of INa and Ito may share common, yet to be identified regulatory mechanisms involving KChIP2, an accessory subunit of Ito. KChIP2 silencing produced simultaneous mRNA degradation and potential translational block of multiple genes at the source of INa and Ito, suggesting a mechanism of microRNA activity, which led to significant loss of Ito and INa. These results suggested KChIP2 may have additional nuclear functions as a transcription factor to regulate other critical cardiac currents. Indeed, a member of the KChIP family found in neuronal tissues, KChIP3, also known as DREAM, is localized to the nucleus where it acts as a Ca2+-regulated transcriptional repressor. Given KChIP2 shares a high degree of sequence homology with DREAM and that it has been found in the nucleus, one can hypothesize that KChIP2 is capable of similar nuclear roles in cardiac settings. Therefore, we hypothesize that KChIP2 controls expression of depolarizing INa and repolarizing Ito through a novel posttranscriptional mechanism involving microRNAs. Indeed, our preliminary data show evidence demonstrating KChIP2 transcriptionally regulates a family of miRNAs known as miR-34s which we demonstrate targets genes involved in generating both INa and Ito. However the significance of this pathway under pathologic conditions is unknown and is the central focus of this proposal. We hypothesize that KChIP2 loss in the diseased heart (hypertrophy and/or HF) is responsible for dysfunction of cardiac excitability at the level of gene expression. Given that KChIP2 is significantly repressed in HF, our specific aims are to: 1. Define the role of KChIP2 miRNA-dependent regulation in cardiac pathology. 2. Evaluate the influence of restored KChIP2 expression on arrhythmia susceptibility and HF progression. 3. Evaluate the influence of miRNA blockade by antagomirs on arrhythmia susceptibility and heart failure progression. To test these aims rat and guinea pig heart failure models produced by transverse aortic constriction (TAC) and the canine pacing-induced HF model will be used. Delivery of either KChIP2 through viral vectors or miR-34 blockade by injection of miRNA antagomirs will be used to assess influence over INa and Ito expression as well as overall arrhythmia susceptibility and HF progression. The delineation of the molecular basis of KChIP2 regulation is essential for an accurate understanding of cardiac depolarization and repolarization and its implications with lethal ventricular arrhythmias.

 描述（由申请人提供）：心律失常是发达国家发病率和死亡率的主要原因。通常，这些心律失常与获得性心脏病相关，特别是心力衰竭（HF），其中观察到许多离子转运蛋白和通道的失调。特别是，观察到去极化INa和复极化Ito两者的临界不平衡。我们以前的工作是第一个支持新生的想法，表达的INa和伊藤可能有共同的，尚未确定的监管机制，涉及KChIP 2，一个附属亚基的伊藤。KChIP 2沉默导致INa和Ito来源的多个基因的同时mRNA降解和潜在的翻译阻断，表明microRNA活性的机制，这导致Ito和INa的显著损失。这些结果表明，KChIP 2可能具有额外的核功能，作为转录因子调节其他关键的心脏电流。事实上，在神经元组织中发现的KChIP家族的成员KChIP 3，也称为DREAM，定位于细胞核，在那里它作为Ca 2+调节的转录抑制因子。鉴于KChIP 2与DREAM具有高度的序列同源性，并且已在细胞核中发现，因此可以假设KChIP 2能够在心脏环境中发挥类似的核作用。因此，我们假设KChIP 2通过一种涉及microRNA的新型转录后机制控制去极化INa和复极化Ito的表达。事实上，我们的初步数据显示，有证据表明KChIP 2转录调节一个称为miR-34的miRNA家族，我们证明该家族靶向参与产生INa和Ito的基因。然而，这一途径在病理条件下的意义是未知的，这是本提案的中心焦点。我们假设，KChIP 2损失在患病的心脏（肥大和/或HF）是负责在基因表达水平的心脏兴奋性功能障碍。鉴于KChIP 2在HF中被显著抑制，我们的具体目标是：1。确定KChIP 2 miRNA依赖性调节在心脏病理学中的作用。2.评价恢复的KChIP 2表达对心律失常易感性和HF进展的影响。3.评价阿托莫西米阻断miRNA对心律失常易感性和心力衰竭进展的影响。为了测试这些目的，将使用由横向主动脉缩窄（TAC）产生的大鼠和豚鼠心力衰竭模型和犬起搏诱导的HF模型。通过病毒载体递送KChIP 2或通过注射miRNA阻断剂阻断miR-34将用于评估对INa和Ito表达以及总体心律失常易感性和HF进展的影响。描绘KChIP 2调节的分子基础对于准确理解心脏去极化和复极化及其与致死性室性心律失常的关系至关重要。

项目成果

Multilayer control of cardiac electrophysiology by microRNAs.

• DOI: 10.1016/j.yjmcc.2022.02.007
• 发表时间: 2022-05
• 期刊: JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
• 影响因子: 5
• 作者: Yang, Dandan;Desche, Isabelle;Fu, Ji-Dong
• 通讯作者: Fu, Ji-Dong

Inhibition of CREB-CBP Signaling Improves Fibroblast Plasticity for Direct Cardiac Reprogramming.

• DOI: 10.3390/cells10071572
• 发表时间: 2021-06-22
• 期刊: Cells
• 影响因子: 6
• 作者: Bektik E;Sun Y;Dennis AT;Sakon P;Yang D;Deschênes I;Fu JD
• 通讯作者: Fu JD

KChIP2 regulates the cardiac Ca2+ transient and myocyte contractility by targeting ryanodine receptor activity.

• DOI: 10.1371/journal.pone.0175221
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Nassal DM;Wan X;Liu H;Laurita KR;Deschênes I
• 通讯作者: Deschênes I

S-phase Synchronization Facilitates the Early Progression of Induced-Cardiomyocyte Reprogramming through Enhanced Cell-Cycle Exit.

• DOI: 10.3390/ijms19051364
• 发表时间: 2018-05-04
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Bektik E;Dennis A;Pawlowski G;Zhou C;Maleski D;Takahashi S;Laurita KR;Deschênes I;Fu JD
• 通讯作者: Fu JD