title: Induction of endoplasmic reticulum stress impairs insulin-stimulated vasomotor relaxation in rat aortic rings: role of endothelin-1.
abstract: Sustained endoplasmic reticulum (ER) stress and thus activation of the unfolded protein response is now thought to be the foundation of various chronic disorders including whole-body insulin resistance and cardiovascular disease. The purpose of the present study was to test the hypothesis that ER stress impairs insulin-stimulated vasomotor reactivity. We report that experimental induction of ER stress in isolated aortic rings with tunicamycin (20 μg/mL), a well-established inducer of ER stress, resulted in insulin-stimulated vascular contraction (-78±21% at 1000 μIU/mL; -100±27% at 10,000 μIU/mL; all p<0.05) rather than relaxation (+23±7% at 1000 μIU/mL; +43±8% at 10,000 μIU/mL; all p<0.05). Importantly, we found that insulin-stimulated vascular contraction as a result of ER stress was largely eliminated in the presence of tezosentan (3 μM), a nonselective endothelin-1 (ET-1) receptor blocker (+1±14% at 1000 μIU/mL; +8±17% at 10,000 μIU/mL). Similarly, inhibition of ET-1 receptors fully restored the impairment of acetylcholine-mediated relaxation induced by ER stress (maximal relaxation: control = 94±2%, tunicamycin = 76±5%, tunicamycin + tezosentan = 90±3). Furthermore, we demonstrate that ER stress caused a ≈20-fold greater release of ET-1 from aortic endothelial cells under basal conditions as well as a ≈15-fold increase under insulin-stimulated conditions (p<0.05). This ER stress-mediated up-regulation in ET-1 release from endothelial cells was accompanied by a ≈3-fold increase in phosphorylation of p44/22 MAPK (p<0.05), a known pathway by which insulin signaling activates ET-1. Together, these findings support the hypothesis that vascular ER stress-mediated activation of ET-1 may be an underlying cause of impaired vasomotor responsiveness to insulin and endothelial dysfunction.
authors.affiliation: Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA. padillaja@missouri.edu.
authors.forename: J
authors.initials: J
authors.lastname: Padilla
authors.forename: N T
authors.initials: NT
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology*; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism; D019332:Endothelin-1 / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D019332:Endothelin-1; D007328:Insulin