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和死亡的主要原因，这些心律失常通常与后天性心脏病，特别是心力衰竭（HF）有关，其中许多离子转运蛋白和离子转运蛋白的失调。特别是，观察到去极化 INa 和复极化 Ito 的严重不平衡，我们之前的工作首次支持了 INa 表达的新观点。和 Ito 可能具有共同的、尚未确定的调节机制 KChIP2，涉及 Ito 的辅助亚基在 INa 和 Ito 的源头同时产生 mRNA 降解和多个基因的潜在翻译阻断，这表明 microRNA 活性的机制，从而导致。这些结果表明 KChIP2 可能具有额外的核功能，作为调节其他关键心脏电流的转录因子，它是在神经元组织中发现的 KChIP 家族的成员。 KChIP3，也称为 DREAM，定位于细胞核，充当 Ca2+ 调节的转录抑制子。鉴于 KChIP2 与 DREAM 具有高度的序列同源性，并且已在细胞核中发现它，因此可以知道 KChIP2 是。因此，我们研究 KChIP2 通过涉及 microRNA 的新型转录后机制控制去极化 INa 和复极化 Ito 的表达。我们的初步数据表明，KChIP2 转录调控了一个称为 miR-34 的 miRNA 家族，我们证明了该家族参与产生 INa 和 Ito 的靶基因，但该通路在病理条件下的重要性尚不清楚，这是本提案的核心焦点。我们认为，患病心脏（肥大和/或心力衰竭）中 KChIP2 的缺失是基因表达水平上心脏兴奋性功能障碍的原因，因为 KChIP2 在心力衰竭中受到显着抑制。我们的具体目标是： 1. 确定 KChIP2 miRNA 依赖性调节在心脏病理学中的作用 2. 评估恢复的 KChIP2 表达对心律失常易感性和心力衰竭进展的影响 3. 评估 miRNA 阻断对心律失常易感性的影响。为了测试这些目标，使用横向主动脉缩窄产生的大鼠和豚鼠心力衰竭模型。 (TAC) 和犬起搏诱导的心力衰竭模型将用于通过病毒载体递送 KChIP2 或通过注射 miRNA antagomir 阻断 miR-34，以评估对 INa 和 Ito 表达以及总体心律失常易感性的影响。心力衰竭进展的描述对于准确理解心脏去极化和复极化及其对致命心室的影响至关重要。心律失常。

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