Deletion of Endoplasmic Reticulum Stress-Induced CHOP Protects Microvasculature Post-Spinal Cord Injury

Janelle      M. Fassbender; Sujata      Saraswat-Ohri; Scott      A. Myers; Mark      J. Gruenthal; Richard      L. Benton; Scott      R. Whittemore

doi:10.2174/156720212803530627

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.

Keywords: Angiogenesis, CHOP, endoplasmic reticulum stress, endothelial cell, inflammation, spinal cord injury, (TRAF2), (HAECs), (PERK), (ECs)