Mechnaisms of Late Sodium Current in Failing Heart

心力衰竭晚期钠电流的机制

• 批准号: 7087766
• 负责人: ALBERTAS I UNDROVINAS
• 金额: $ 20.95万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087766
• 关键词: arrhythmia; calmodulin; calmodulin dependent protein kinase; cardiac myocytes; cytoskeleton; dogs; heart failure; heart ventricle; mathematical model; messenger RNA; myocardium; oligonucleotides; polymerase chain reaction; sodium channel; tissue /cell culture; voltage /patch clamp; western blottings

DESCRIPTION (provided by applicant): Heart failure (HF) is associated with a significant incidence of lethal cardiac arrhythmias. The molecular mechanisms accounting for these arrhythmias are incompletely defined and will be the basis of study for this new, four-year application. The slower and larger late sodium current (INaL) was originally described by our laboratory in normal and failing hearts and has been recognized as an important contributor to arrhythmia generation. The molecular origin and regulatory mechanisms of INaL, particularly in diseased myocardium, remain largely unknown and will serve as the focus of this proposal. The specific aims of this proposal will test the following hypotheses: 1) the main a-subunit of the cardiac Na+ channel isoform operates in distinct gating modes and is responsible for INaL in normal and failing myocardium, 2) INaL can be regulated by the membrane micro-environment of the channel, namely by the cytoskeleton and auxiliary beta-subunits, and 3) INaL can be modulated by intracellular signaling pathways involving the Ca2+-sensing protein, calmodulin. Ventricular canine cardiomyocytes isolated from normal hearts and hearts from dogs with chronic HF produced by sequential coronary microembolizations will be used to execute the specific aims. Whole-cell and single-channel voltage clamp techniques will be employed to study the activity of the late Na+ channels in cultured cardiomyocytes with knocked-down genes and/or altered cell-signaling pathways. Knowledge derived from the present proposal may reveal novel targets for the treatment of life-threatening arrhythmias associated with chronic HF.

描述（由申请人提供）：心力衰竭（HF）与致命心律不齐的显着发生率有关。考虑到这些心律不齐的分子机制未完全定义，这将是该新的四年应用的研究基础。我们的实验室在正常和失败的心脏中最初描述了较慢，较大的晚期钠电流（INAL），并被认为是心律不齐产生的重要贡献者。 INAL的分子起源和调节机制，尤其是在心肌心肌中，在很大程度上尚不清楚，并将作为该提案的重点。 The specific aims of this proposal will test the following hypotheses: 1) the main a-subunit of the cardiac Na+ channel isoform operates in distinct gating modes and is responsible for INaL in normal and failing myocardium, 2) INaL can be regulated by the membrane micro-environment of the channel, namely by the cytoskeleton and auxiliary beta-subunits, and 3) INaL can be modulated by涉及Ca2+传感蛋白的细胞内信号通路，钙调蛋白。从正常的心脏和心脏中分离出的心脏和心脏的心室心肌细胞，这些犬将使用顺序冠状动脉微栓塞产生的慢性HF，以执行特定目的。将采用全电池和单通道电压夹技术来研究以敲低基因和/或改变细胞信号途径的培养的心肌细胞中晚期Na+通道的活性。从本提案中得出的知识可能揭示了治疗与慢性HF相关的威胁生命心律不齐的新目标。

项目成果

Late sodium current contributes to diastolic cell Ca2+ accumulation in chronic heart failure.

• DOI: 10.1007/s12576-010-0092-0
• 发表时间: 2010-07
• 期刊: JOURNAL OF PHYSIOLOGICAL SCIENCES
• 影响因子: 2.3
• 作者: Undrovinas, Nidas A.;Maltsev, Victor A.;Belardinelli, Luiz;Sabbah, Hani N.;Undrovinas, Albertas
• 通讯作者: Undrovinas, Albertas