Despite the extensive research and novel treatments, human systolic heart failure (HF) remains a substantial clinical problem affecting millions of Americans and HF associated arrhythmia still remains a cause of the high morbidity and mortality. Recently, three SCN5a cardiac Na+ channel mRNA alternative splicing variants were found to be upregulated in human HF tissue. These splicing variants resulted from splicing at cryptic splice sequences in the terminal exon of SCN5a (i.e., exon 28) and encoded cardiac Na+ channels truncated before the pore forming segment of domain IV. Variant levels reached greater that >50% of the total SCN5a mRNA. As expected, these variants did not form functional channels. Moreover, the presence of the variants caused reduced abundance of the full-length SCN5a mRNA without alteration of total SCN5a mRNA. This application proposes to establish the mechanism whereby the abnormal splicing occurs in HF and how the presence of truncated Na+ channel variants causes a dominant negative downregulation of the full-length channel mRNA. Preliminary data suggest hypoxia and angiotensin II (AngII) can signal pathological SCN5a splicing regulation by inducing expression of the mRNA splicing factor, CROP/hLuc7A, and its co-factor RBM25, which alter SCN5a splicing regulation by interacting with one or more RBM25 binding sequences CGGGC(A) in SCN5a exon 28, the exon where abnormal splicing of SCN5a occurs. Furthermore, data show that truncated Na+ channels accumulate in endoplasmic reticulum (ER) and initiate the unfolded protein response (UPR) pathway, causing reduced Na+ channel translation and a shortened half-life of the full-length SCN5a transcript. Hypothesis. Based on the above, we hypothesized that the hLuc7A/RBM25 complex contributes to abnormal Na+ channel mRNA splicing and that the UPR contributes to the dominant negative effect the abnormally spliced transcripts have on the Na+ channel. Specific Objectives.
Specific aim 1 : To establish whether the hLuc7A/RBM25 splicing regulation pathway is involved in the mechanism to increase SCN5a mRNA variant expression.
Specific aim 2 : To determine to what extent the three major pathways in the unfolded protein response (UPR) are responsible for the reduction in functional Na+ channels.
Specific aim 3 : To demonstrate the relationship of hLuc7A/RBM25 regulation, the unfolded protein response (UPR) activation, Na+ channel mRNA variants, and Na+ channel measures in human heart failure samples.

Public Health Relevance

The cause of sudden death in heart failure is unknown. This application will explore one potential cause, abnormal sodium channel processing, establishing the mechanism and possible elucidating prevention strategies. Moreover, if white cells show similar abnormalities, this work may lead to a blood test to predict sudden death risk in heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Wang, Lan-Hsiang
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University of Illinois at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Zhou, Anyu; Shi, Guangbin; Kang, Gyeoung-Jin et al. (2018) RNA Binding Protein, HuR, Regulates SCN5A Expression Through Stabilizing MEF2C transcription factor mRNA. J Am Heart Assoc 7:
Zhou, Anyu; Xie, An; Kim, Tae Yun et al. (2018) HuR-mediated SCN5A messenger RNA stability reduces arrhythmic risk in heart failure. Heart Rhythm 15:1072-1080
Xie, An; Zhou, Anyu; Liu, Hong et al. (2018) Mitochondrial Ca2+ flux modulates spontaneous electrical activity in ventricular cardiomyocytes. PLoS One 13:e0200448
Liu, Man; Shi, Guangbin; Zhou, Anyu et al. (2018) Activation of the unfolded protein response downregulates cardiac ion channels in human induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol 117:62-71
Vang, Alexander; Clements, Richard T; Chichger, Havovi et al. (2017) Effect of ?7 nicotinic acetylcholine receptor activation on cardiac fibroblasts: a mechanism underlying RV fibrosis associated with cigarette smoke exposure. Am J Physiol Lung Cell Mol Physiol 312:L748-L759
Noyes, Adam M; Zhou, Anyu; Gao, Ge et al. (2017) Abnormal sodium channel mRNA splicing in hypertrophic cardiomyopathy. Int J Cardiol 249:282-286
Liu, Man; Shi, Guangbin; Yang, Kai-Chien et al. (2017) Role of protein kinase C in metabolic regulation of the cardiac Na+ channel. Heart Rhythm 14:440-447
Kim, Tae Yun; Terentyeva, Radmila; Roder, Karim H F et al. (2017) SK channel enhancers attenuate Ca2+-dependent arrhythmia in hypertrophic hearts by regulating mito-ROS-dependent oxidation and activity of RyR. Cardiovasc Res 113:343-353
Jiang, Ning; Zhou, Anyu; Prasad, Bharati et al. (2016) Obstructive Sleep Apnea and Circulating Potassium Channel Levels. J Am Heart Assoc 5:
Liu, M; Yang, K-C; Dudley Jr, S C (2016) Cardiac Sodium Channel Mutations: Why so Many Phenotypes? Curr Top Membr 78:513-59

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