title: Deletion of endoplasmic reticulum stress-induced CHOP protects microvasculature post-spinal cord injury.
abstract: Trauma introduces damaging stressors that compromise protein, lipid, and nucleic acid integrity. Aggregates of unfolded and misfolded proteins in the endoplasmic reticulum (ER) triggers the ER stress response (ERSR)/unfolded protein response (UPR) leading to activation of three signaling pathways mediated by PERK, ATF6, and IRE1. Initially, the ERSR/UPR is pro-homeostatic as it globally slows translation while increasing translation of chaperone proteins and inducing ER-associated degradation. If the cellular stress is not controlled, apoptosis is subsequently induced through several mechanisms, of which the most well-described is CHOP. Following spinal cord injury (SCI), mice deficient in CHOP signaling show increased spared white matter and enhanced locomotor recovery by 6 weeks. At 24 hours after SCI, ATF4 and CHOP are upregulated in under perfused microvessels. We observed vascular protection 3 days post-SCI and a significant decrease in macrophage infiltration by the end of the first week. These results suggest that modulating ER-stress signaling in endothelial cells and macrophages may protect against vascular injury and attenuate inflammation post-SCI.
authors.affiliation: Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY 40292, USA.
authors.forename: Janelle M
authors.initials: JM
authors.lastname: Fassbender
authors.forename: Sujata
authors.initials: S
authors.lastname: Saraswat-Ohri
authors.forename: Scott A
authors.initials: SA
authors.lastname: Myers
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Gruenthal
authors.forename: Richard L
authors.initials: RL
authors.lastname: Benton
authors.forename: Scott R
authors.initials: SR
authors.lastname: Whittemore
mesh_terms: D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000235:genetics* / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009043:Motor Activity / Q000235:genetics; D009044:Motor Cortex / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013904:Thoracic Vertebrae; D051742:Transcription Factor CHOP / Q000172:deficiency* / Q000235:genetics
chemical_list: C497250:Ddit3 protein, mouse; D018696:Neuroprotective Agents; D051742:Transcription Factor CHOP