ArticleCirculation research2016
NF2 Activates Hippo Signaling and Promotes Ischemia/Reperfusion Injury in the Heart.
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Article in Circulation research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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82 citing papers in PubMed, 127 citations in OpenAlex.
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- TEAD-independent mechanisms of YAP function in cardiomyocyte cell cycle reentry.Life science alliance · 2026Article
- Silencing soluble epoxide hydrolase protects against myocardial ischemia-reperfusion injury through modulation of the YAP signaling pathway and macrophage polarization.Journal of molecular histology · 2026Article
- The role of Mir-365-5p in regulating NF2-Mediated apoptosis and ROS production in hypoxic cardiomyoblasts.Molecular biology reports · 2025Article
- Cell type specificity of Hippo-YAP signaling in cardiac development and disease.Journal of molecular and cellular cardiology · 2025Review
- Nf2/FGFR1/AKT axis directs cranial neural crest-derived skull morphogenesis via collagen synthesis and trafficking.JCI insight · 2025Article
- Cardiomyocyte YAP represses myocardial inflammation and fibrosis and restrains MEF2-regulated gene expression.American journal of physiology. Heart and circulatory physiology · 2025Article
- MiR-1291 mediates the protective effect of sevoflurane preconditioning against hypoxia/reoxygenation-induced myocardial cell injury.Toxicology research · 2025Article
- Posttranslational modifications of YAP/TAZ: molecular mechanisms and therapeutic opportunities.Cellular & molecular biology letters · 2025Review
- Maresin1 Alleviates Ischemia Reperfusion Injury After Lung Transplantation by Inhibiting Ferroptosis via the PKA-Hippo-YAP Signaling Pathway.Biomedicines · 2025Article
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- YAP/TAZ as mechanobiological signaling pathway in cardiovascular physiological regulation and pathogenesis.Mechanobiology in medicine · 2024Article
- The Multifaceted Roles of Hippo-YAP in Cardiovascular Diseases.Cardiovascular toxicology · 2024Review
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- Melatonin regulates mitochondrial dynamics and mitophagy: Cardiovascular protection.Journal of cellular and molecular medicine · 2024Review
- Exploring the versatility of miRNA-128: a comprehensive review on its role as a biomarker and therapeutic target in clinical pathways.Molecular biology reports · 2024Review
- Injectable Peptide Hydrogels Loaded with Murine Embryonic Stem Cells Relieve IschemiaBiomacromolecules · 2024Article
- Insufficient autophagy enables the nuclear factor erythroid 2-related factor 2 (NRF2) to promote ferroptosis in morphine-treated SH-SY5Y cells.Psychopharmacology · 2024Article
- Xinnaotongluo liquid protects H9c2 cells from H/R-induced damage by regulating MDM2/STEAP3.PloS one · 2024Article
22 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 4 institutions in 3 countries.
Takahisa MatsudaFrom the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
Peiyong ZhaiFrom the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
Sebastiano SciarrettaFrom the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
Yu ZhangFrom the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
Jae Im JeongFrom the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
Shohei IkedaFrom the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
Jiyeon ParkFrom the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
Chiao-Po HsuFrom the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
Bin TianFrom the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
Duojia PanFrom the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
Junichi SadoshimaFrom the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.).
Dominic P Del ReFrom the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers, New Jersey Medical School, Newark (T.M., P.Z., Y.Z., J.I.J., S.I., J.S., D.P.D.R.); Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers, New Jersey Medical School, Newark (J.P., B.T.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS) (S.S.) and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina, Italy (S.S.); Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); and Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.). delredo@njms.rutgers.edu.
National Yang Ming Chiao Tung University · TWIstituto Neurologico Mediterraneo · ITTaipei Veterans General Hospital · TWRutgers New Jersey Medical School
Funding
Cysteine oxidation in the heartR01HL091469 · NHLBI · UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL · PI Junichi Sadoshima · 2008 to 2026
$9.4MThe Role of Serine Signaling in Compensatory Cardiac HypertrophyR01HL112330 · NHLBI · UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL · PI Junichi Sadoshima · 2012 to 2026
$7.5MThe Role of Thioredoxin in the Aging HeartR01AG023039 · NIA · UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL · PI SADOSHIMA, JUNICHI · 2004 to 2018
$5.8MRegulation of myocardial growth and death by GSK-3R01HL067724 · NHLBI · UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL · PI SADOSHIMA, JUNICHI · 2000 to 2018
$5.1MRegulation of myocardial growth and death by autophagyR01HL102738 · NHLBI · UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL · PI SADOSHIMA, JUNICHI · 2010 to 2014
$2.5MThe role of NF2 in myocardial ischemia and reperfusion injuryR01HL127339 · NHLBI · RBHS-NEW JERSEY MEDICAL SCHOOL · PI DEL RE, DOMINIC P · 2015 to 2019
$2.0MThe role of RASSF1A in myocardial ischemia/reperfusion injuryR21HL122669 · NHLBI · RBHS-NEW JERSEY MEDICAL SCHOOL · PI DEL RE, DOMINIC P · 2013 to 2013
$159kNHLBI NIH HHS R01 HL067724NHLBI NIH HHS R01 HL091469NHLBI NIH HHS R01 HL102738NHLBI NIH HHS R01 HL112330NHLBI NIH HHS R01 HL127339NHLBI NIH HHS R21 HL122669NIA NIH HHS R01 AG023039
Abstract
rationaleNF2 (neurofibromin 2) is an established tumor suppressor that promotes apoptosis and inhibits growth in a variety of cell types, yet its function in cardiomyocytes remains largely unknown.
objectiveWe sought to determine the role of NF2 in cardiomyocyte apoptosis and ischemia/reperfusion (I/R) injury in the heart. METHODS AND
resultsWe investigated the function of NF2 in isolated cardiomyocytes and mouse myocardium at baseline and in response to oxidative stress. NF2 was activated in cardiomyocytes subjected to H2O2 and in murine hearts subjected to I/R. Increased NF2 expression promoted the activation of Mst1 (mammalian sterile 20-like kinase 1) and the inhibition of Yap (Yes-associated protein), whereas knockdown of NF2 attenuated these responses after oxidative stress. NF2 increased the apoptosis of cardiomyocytes that appeared dependent on Mst1 activity. Mice deficient for NF2 in cardiomyocytes, NF2 cardiomyocyte-specific knockout (CKO), were protected against global I/R ex vivo and showed improved cardiac functional recovery. Moreover, NF2 cardiomyocyte-specific knockout mice were protected against I/R injury in vivo and showed the upregulation of Yap target gene expression. Mechanistically, we observed nuclear association between NF2 and its activator MYPT-1 (myosin phosphatase target subunit 1) in cardiomyocytes, and a subpopulation of stress-induced nuclear Mst1 was diminished in NF2 CKO hearts. Finally, mice deficient for both NF2 and Yap failed to show protection against I/R indicating that Yap is an important target of NF2 in the adult heart.
conclusionsNF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through the activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart.
Indexed as
AnimalsApoptosisCells, CulturedHippo Signaling PathwayHydrogen PeroxideMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicMyocardial Reperfusion InjuryMyocytes, CardiacNeurofibromin 2Protein Serine-Threonine KinasesSignal TransductionHydrogen PeroxideNeurofibromin 2Protein Serine-Threonine Kinasesapoptosiscardiomyocyteneurofibromin 2oxidative stressreperfusion injury
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