ArticleCardiovascular research2023
Ryanodine receptor 2 (RYR2) dysfunction activates the unfolded protein response and perturbs cardiomyocyte maturation.
Article in Cardiovascular research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 28 citations in OpenAlex.
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- Loss of Echs1 in neural stem and progenitor cells impairs neurogenesis via ER stress activation and lipid metabolic reprogramming.Nature communications · 2026Article
- The RyR-like-FKBP12-PKA Complex Regulates Intracellular CaInternational journal of molecular sciences · 2026Article
- Review
- Tumor Intrinsic METTL5 Modulates ATF4 Translation to Prevent T Cell-Induced Ferroptosis in Ovarian Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Arrhythmogenic Risk in iPSC-Derived Cardiomyocytes: Current Limitations and Therapeutic Perspectives.Medicina (Kaunas, Lithuania) · 2025Review
- Molecular gatekeepers of endogenous adult mammalian cardiomyocyte proliferation.Nature reviews. Cardiology · 2025Review
- Ufmylation Suppresses Unfolded Protein Response to Prevent Peripartum Cardiomyopathy.JACC. Basic to translational science · 2025Article
- Developmental cues from epicardial cells simultaneously promote cardiomyocyte proliferation and electrochemical maturation.Stem cell reports · 2025Article
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- Electrophysiological Mechanisms and Therapeutic Potential of Calcium Channels in Atrial Fibrillation.Reviews in cardiovascular medicine · 2025Review
- Rapid and robust generation of cardiomyocyte-specific crispants in zebrafish using the cardiodeleter system.Cell reports methods · 2025Article
- Extracorporeal membrane oxygenation for catecholaminergic polymorphic ventricular tachycardia: a case report and literature review.BMC pediatrics · 2025Review
- Beyond the Beat, Next-Generation Sequencing Discovery of NovelCardiology research and practice · 2025Article
- The Low Tumorigenic Risk and Subtypes of Cardiomyocytes Derived from Human-induced Pluripotent Stem Cells.Current stem cell research & therapy · 2025Article
- The modulation of calcium and chloride channels induces cardiomyocytes from human pluripotent stem cells.International journal of biological sciences · 2025Article
- Non-Cell-Autonomous Cardiomyocyte Regulation Complicates Gene Supplementation Therapy forJACC. Basic to translational science · 2024Article
- Hyperactivation of ATF4/TGF-β1 signaling contributes to the progressive cardiac fibrosis in Arrhythmogenic cardiomyopathy caused by DSG2 Variant.BMC medicine · 2024Article
- Single-cell RNA sequencing in donor and end-stage heart failure patients identifies NLRP3 as a therapeutic target for arrhythmogenic right ventricular cardiomyopathy.BMC medicine · 2024Article
- Cypher/ZASP drives cardiomyocyte maturation via actin-mediated MRTFA-SRF signalling.Theranostics · 2024Article
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Authors and funding
17 authors at 3 institutions in 3 countries.
Funding
Abstract
aimsCalcium-handling capacity is a major gauge of cardiomyocyte maturity. Ryanodine receptor 2 (RYR2) is the pre-dominant calcium channel that releases calcium from the sarcoplasmic reticulum/endoplasmic reticulum (SR/ER) to activate cardiomyocyte contraction. Although RYR2 was previously implied as a key regulator of cardiomyocyte maturation, the mechanisms remain unclear. The aim of this study is to solve this problem. METHODS AND
resultsWe performed Cas9/AAV9-mediated somatic mutagenesis to knockout RYR2 specifically in cardiomyocytes in mice. We conducted a genetic mosaic analysis to dissect the cell-autonomous function of RYR2 during cardiomyocyte maturation. We found that RYR2 depletion triggered ultrastructural and transcriptomic defects relevant to cardiomyocyte maturation. These phenotypes were associated with the drastic activation of ER stress pathways. The ER stress alleviator tauroursodeoxycholic acid partially rescued the defects in RYR2-depleted cardiomyocytes. Overexpression of ATF4, a key ER stress transcription factor, recapitulated defects in RYR2-depleted cells. Integrative analysis of RNA-Seq and bioChIP-Seq data revealed that protein biosynthesis-related genes are the major direct downstream targets of ATF4.
conclusionRYR2-regulated ER homeostasis is essential for cardiomyocyte maturation. Severe ER stress perturbs cardiomyocyte maturation primarily through ATF4 activation. The major downstream effector genes of ATF4 are related to protein biosynthesis.
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