Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin-cardiomyopathy mice
Atsuki En,
Hanumakumar Bogireddi,
Briana Thomas,
Alexis V. Stutzman,
Sachie Ikegami,
Brigitte LaForest,
Omar Almakki,
Peter Pytel,
Ivan P. Moskowitz,
Kohta Ikegami
Affiliations
Atsuki En
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
Hanumakumar Bogireddi
Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Briana Thomas
Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Alexis V. Stutzman
Department of Pediatrics, the University of Chicago, Chicago, IL 60637, USA
Sachie Ikegami
Department of Pediatrics, the University of Chicago, Chicago, IL 60637, USA
Brigitte LaForest
Department of Pediatrics, the University of Chicago, Chicago, IL 60637, USA
Omar Almakki
Department of Pediatrics, the University of Chicago, Chicago, IL 60637, USA
Peter Pytel
Department of Pathology, the University of Chicago, Chicago, IL 60637, USA
Ivan P. Moskowitz
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
Kohta Ikegami
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; Corresponding author
Summary: 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.
