| Title: |
Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin-cardiomyopathy mice |
| Authors: |
En, Atsuki; Bogireddi, Hanumakumar; Thomas, Briana; Stutzman, Alexis V.; Ikegami, Sachie; LaForest, Brigitte; Almakki, Omar; Pytel, Peter; Moskowitz, Ivan P.; Ikegami, Kohta |
| Source: |
Cell Reports, 43(6) |
| Publisher Information: |
Elsevier |
| Publication Year: |
2024 |
| Collection: |
Carolina Digital Repository (UNC - University of North Carolina) |
| Subject Terms: |
extracellular matrix; communication; near absence; cardio-myocytes; cardiomyocytes; fatal dilated cardiomyopathy; hypothesis; dilated cardiomyopathy; inflammatory contributors; adult mice; cGAS-STING; A/C; pathway; activate cGAS-STING; lack; reduction; transcription; cardiomyopathy; inflammatory transcripts; cardiomyocyte death; envelope; mouse model; death; DNA-sensing pathway; NE rupture; envelope rupture; nuclear lamina components; expression; adult-onset disease; mutations |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
unknown |
| Relation: |
https://cdr.lib.unc.edu/downloads/zs25xp848?file=thumbnail; https://cdr.lib.unc.edu/downloads/zs25xp848 |
| DOI: |
10.17615/d08t-ce52 |
| Availability: |
https://doi.org/10.17615/d08t-ce52; https://cdr.lib.unc.edu/downloads/zs25xp848?file=thumbnail; https://cdr.lib.unc.edu/downloads/zs25xp848 |
| Rights: |
http://rightsstatements.org/vocab/InC/1.0/ ; http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.B01C79B9 |
| Database: |
BASE |