SUN-270 - Endoplasmic Reticulum Is A Master Regulator of Cellular Stress

Endoplasmic reticulum (ER) stress, oxidative stress, and inflammatory stress play pivotal roles in propagating various diseases including cardiovascular disease. It is unclear, however, how these three stressors interact. To evaluate the cross talk between these stressors a series of experiments were carried out in human coronary artery endothelial cells (HCAEC). Treatment of HCAEC with the ER stress inducers tunicamycin and thapsigargin increased SO generation after 24 hours; these effects were suppressed by alpha-tocopherol and ascorbic acid, and by the ER stress inhibitors 4-phenylbutyrate and tauroursodeoxycholic acid. The increased oxidative stress in cells treated with tunicamycin and thapsigargin, was associated with increased secretion of inflammatory cytokines notably TNFalpha, IL-1beta, IL-6, and IL-8, but not IL-2, while amelioration of ER stress with GSK2850163 [an inositol requiring enzyme 1alpha (IRE1alpha inhibitor] and GSK2606414 [a protein kinase R-like endoplasmic reticulum kinase (PERK) inhibitor], but not Ceapin A7 [an activating transcription factor 6 (ATF6 inhibitor)], normalized inflammatory cytokine release. These observations indicate that the IRE1alpha and PERK branches of the unfolded protein response (UPR) and not ATF6, modulate pro-inflammatory cytokine release. Overall, it appears that inflammatory stress can be the result of oxidative stress and ER stress and the latter effect could be a direct or indirect effect through ER instigated oxidative stress. These data along with the previously published studies showing that antioxidants can aggravate ER stress highlight the critical role of ER stress as a master regulator of total cellular stress.

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