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Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin-cardiomyopathy mice.
En, Atsuki; Bogireddi, Hanumakumar; Thomas, Briana; Stutzman, Alexis V; Ikegami, Sachie; LaForest, Brigitte; Almakki, Omar; Pytel, Peter; Moskowitz, Ivan P; Ikegami, Kohta.
Afiliación
  • En A; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Graduate School of Nanobioscience, Yokohama City University, Yokohama, Kanagawa 236-0027, Japan.
  • Bogireddi H; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • Thomas B; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • Stutzman AV; Department of Pediatrics, the University of Chicago, Chicago, IL 60637, USA.
  • Ikegami S; Department of Pediatrics, the University of Chicago, Chicago, IL 60637, USA.
  • LaForest B; Department of Pediatrics, the University of Chicago, Chicago, IL 60637, USA.
  • Almakki O; Department of Pediatrics, the University of Chicago, Chicago, IL 60637, USA.
  • Pytel P; Department of Pathology, the University of Chicago, Chicago, IL 60637, USA.
  • Moskowitz IP; Department of Pediatrics, the University of Chicago, Chicago, IL 60637, USA; Department of Pathology, the University of Chicago, Chicago, IL 60637, USA; Department of Human Genetics, the University of Chicago, Chicago, IL 60637, USA.
  • Ikegami K; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Electronic address: kohta.ikegami@cchmc.org.
Cell Rep ; 43(6): 114284, 2024 Jun 25.
Article en En | MEDLINE | ID: mdl-38814785
ABSTRACT
Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin A/C, a nuclear lamina component. Here, we test a prevailing hypothesis that NE ruptures trigger the pathological cGAS-STING cytosolic DNA-sensing pathway using a mouse model of Lamin cardiomyopathy. The reduction of Lamin A/C in cardio-myocyte of adult mice causes pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures are followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remains inactive. Deleting cGas or Sting does not rescue cardiomyopathy in the mouse model. The lack of cGAS-STING activation is likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling is activated and predicted to initiate pro-inflammatory communication from Lamin-reduced cardiomyocytes to fibroblasts. Our work nominates ECM signaling, not cGAS-STING, as a potential inflammatory contributor in Lamin cardiomyopathy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Miocitos Cardíacos / Matriz Extracelular / Proteínas de la Membrana / Membrana Nuclear / Nucleotidiltransferasas Límite: Animals Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Miocitos Cardíacos / Matriz Extracelular / Proteínas de la Membrana / Membrana Nuclear / Nucleotidiltransferasas Límite: Animals Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos