ArticleCirculation. Arrhythmia and electrophysiology2013
Unfolded protein response regulates cardiac sodium current in systolic human heart failure.
Article in Circulation. Arrhythmia and electrophysiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 72 citations in OpenAlex.
- Enhanced risk profiling of implanted defibrillator shocks with circulating SCN5A mRNA splicing variants: a pilot trial.Journal of the American College of Cardiology · 2014Trial
- Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy.Signal transduction and targeted therapy · 2026Review
- Signal Recognition Granule Receptor Beta Subunit Promotes Arrhythmogenic Remodeling in the Heart Failure Mice.Journal of the American Heart Association · 2026Article
- A Human Engineered Heart Tissue-Derived Lipotoxic Diabetic Cardiomyopathy Model Revealed Early Benefits of Empagliflozin.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Aberrant activation of p53-TRIB3 axis contributes to diabetic myocardial insulin resistance and sulforaphane protection.Journal of advanced research · 2025Article
- The Biological Mechanisms and Clinical Roles of RNA-Binding Proteins in Cardiovascular Diseases.Biomolecules · 2024Review
- Molecular Mechanism of Yangshen Maidong Decoction in the Treatment of Chronic Heart Failure based on Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulations.Cell biochemistry and biophysics · 2024Article
- Lipotoxicity, ER Stress, and Cardiovascular Disease: Current Understanding and Future Directions.Cardiovascular & hematological agents in medicinal chemistry · 2024Review
- Gasdermin D mediates endoplasmic reticulum stress via FAM134B to regulate cardiomyocyte autophagy and apoptosis in doxorubicin-induced cardiotoxicity.Cell death & disease · 2022Article
- Emerging roles of the RNA modifications N6-methyladenosine and adenosine-to-inosine in cardiovascular diseases.Molecular therapy. Nucleic acids · 2022Review
- Preventing unfolded protein response-induced ion channel dysregulation to treat arrhythmias.Trends in molecular medicine · 2022Review
- Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias.International journal of molecular sciences · 2022Review
- ER stress and calcium-dependent arrhythmias.Frontiers in physiology · 2022Review
- Effect Of XBP1 Deficiency In Cartilage On The Regulatory Network Of LncRNA/circRNA-miRNA-mRNA.International journal of biological sciences · 2022Article
- Unfolded protein response during cardiovascular disorders: a tilt towards pro-survival and cellular homeostasis.Molecular and cellular biochemistry · 2021Review
- Inhibition of the unfolded protein response reduces arrhythmia risk after myocardial infarction.The Journal of clinical investigation · 2021Article
- Cardiac Resynchronization and Circulating Markers of Sarcoplasmic Reticulum Calcium Handling and Sudden Death Risk.JACC. Clinical electrophysiology · 2021Review
- Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy.Circulation · 2021Article
- A Heart Failure-AssociatedFrontiers in physiology · 2021Article
- Article
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
backgroundHuman heart failure (HF) increases alternative mRNA splicing of the type V, voltage-gated cardiac Na+ channel α-subunit (SCN5A), generating variants encoding truncated, nonfunctional channels that are trapped in the endoplasmic reticulum. In this work, we tested whether truncated Na+ channels activate the unfolded protein response (UPR), contributing to SCN5A electric remodeling in HF. METHODS AND
resultsUPR and SCN5A were analyzed in human ventricular systolic HF tissue samples and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Cells were exposed to angiotensin II (AngII) and hypoxia, known activators of abnormal SCN5A mRNA splicing, or were induced to overexpress SCN5A variants. UPR effectors, protein kinase R-like ER kinase (PERK), calreticulin, and CHOP, were increased in human HF tissues. Induction of SCN5A variants with AngII or hypoxia or the expression of exogenous variants induced the UPR with concomitant downregulation of Na+ current. PERK activation destabilized SCN5A and, surprisingly, Kv4.3 channel mRNAs but not transient receptor potential cation channel M7 (TRPM7) channel mRNA. PERK inhibition prevented the loss of full-length SCN5A and Kv4.3 mRNA levels resulting from expressing Na+ channel mRNA splice variants.
conclusionsUPR can be initiated by Na+ channel mRNA splice variants and is involved in the reduction of cardiac Na+ current during human HF. Because the effect is not entirely specific to the SCN5A transcript, the UPR may play an important role in downregulation of multiple cardiac genes in HF.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.