ArticleCirculation research2023
PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation.
Article in Circulation research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 14 citations in OpenAlex.
- Evidence for a role of adverse sarcomere signaling in atrial fibrillation induction.Journal of molecular and cellular cardiology plus · 2026Review
- Proteomic Remodeling in the Failing Left Ventricle Adapting to Dyssynchrony.Proteomics. Clinical applications · 2026Article
- Article
- Polarity protein Par3 deficiency promotes metastasis of bladder cancer via interaction of Ppp1r12c.Biology direct · 2026Article
- Perspectives on Clinical Biomarkers Based on the Pathophysiology of Arrhythmias.Journal of arrhythmia · 2025Review
- CKAP4 Promotes Atrial Fibrosis and Enhances Atrial Fibrillation Vulnerability via WNT/β-Catenin Activation.Circulation. Arrhythmia and electrophysiology · 2025Article
- Atrial Cardiomyopathy in Atrial Fibrillation: Mechanistic Pathways and Emerging Treatment Concepts.Journal of clinical medicine · 2025Review
- Luminescent sensing of conformational integrin activation in living cells.Cell reports · 2025Article
- Left atrial reservoir strain as a predictor of cardiac dysfunction in a murine model of pressure overload.Acta physiologica (Oxford, England) · 2025Article
- The calcium awakens: new insights in cardiac gene therapy.Frontiers in endocrinology · 2025Article
- Animal and cellular models of atrial fibrillation: a review.Frontiers in cardiovascular medicine · 2025Review
- The structural and functional effects of myosin regulatory light chain phosphorylation are amplified by increases in sarcomere length and [CaThe Journal of physiology · 2024Article
- Atrial cardiomyopathy revisited-evolution of a concept: a clinical consensus statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asian Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS).Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2024Article
- Activation of the ROCK/MYLK Pathway Affects Complex Molecular and Morphological Changes of the Trabecular Meshwork Associated With Ocular Hypertension.Investigative ophthalmology & visual science · 2024Article
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25 authors at 12 institutions in 4 countries.
Funding
Abstract
backgroundAtrial fibrillation (AF)-the most common sustained cardiac arrhythmia-increases thromboembolic stroke risk 5-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C (protein phosphatase 1 regulatory subunit 12C)-the PP1 (protein phosphatase 1) regulatory subunit targeting MLC2a (atrial myosin light chain 2)-causes hypophosphorylation of MLC2a and results in atrial hypocontractility.
methodsRight atrial appendage tissues were isolated from human patients with AF versus sinus rhythm controls. Western blots, coimmunoprecipitation, and phosphorylation studies were performed to examine how the PP1c (PP1 catalytic subunit)-PPP1R12C interaction causes MLC2a dephosphorylation. In vitro studies of pharmacological MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with electrophysiology studies.
resultsIn human patients with AF, PPP1R12C expression was increased 2-fold versus sinus rhythm controls (
conclusionsPatients with AF exhibit increased levels of PPP1R12C protein compared with controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.
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