title: Mechanism of endoplasmic reticulum stress-induced vascular endothelial dysfunction.
abstract: BACKGROUND
  We recently reported that ER stress plays a key role in vascular endothelial dysfunction during hypertension. In this study we aimed to elucidate the mechanisms by which ER stress induction and oxidative stress impair vascular endothelial function.
  
  
  RESULTS
  We conducted in vitro studies with primary endothelial cells from coronary arteries stimulated with tunicamycin, 1μg/mL, in the presence or absence of two ER stress inhibitors: tauroursodeoxycholic acid (Tudca), 500μg/mL, and 4-phenylbutyric acid (PBA), 5mM. ER stress induction was assessed by enhanced phosphorylation of PERK and eIF2α, and increased expression of CHOP, ATF6 and Grp78/Bip. The ER stress induction increased p38 MAPK phosphorylation, Nox2/4 mRNA levels and NADPH oxidase activity, and decreased eNOS promoter activity, eNOS expression and phosphorylation, and nitrite levels. Interestingly, the inhibition of p38 MAPK pathway reduced CHOP and Bip expressions enhanced by tunicamycin and restored eNOS promoter activation as well as phosphorylation. To study the effects of ER stress induction in vivo, we used C57BL/6J mice and p47phox(-/-) mice injected with tunicamycin or saline. The ER stress induction in mice significantly impaired vascular endothelium-dependent and independent relaxation in C57BL/6J mice compared with p47phox(-/-) mice indicating NADPH oxidase activity as an intermediate for ER stress in vascular endothelial dysfunction.
  
  
  CONCLUSIONS
  We conclude that chemically induced ER stress leads to a downstream enhancement of p38 MAPK and oxidative stress causing vascular endothelial dysfunction. Our results indicate that inhibition of ER stress could be a novel therapeutic strategy to attenuate vascular dysfunction during cardiovascular diseases.
authors.affiliation: Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, 1430 Tulane Ave, New Orleans, LA 70112, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Galán
authors.affiliation: Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, 1430 Tulane Ave, New Orleans, LA 70112, USA.
authors.forename: Modar
authors.initials: M
authors.lastname: Kassan
authors.affiliation: Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, 1430 Tulane Ave, New Orleans, LA 70112, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kadowitz
authors.affiliation: Nanobioscience Constellation, College of Nanoscale Science and Engineering, State University of New York (SUNY), 257 Fuller Rd., Albany, NY 12203, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Trebak
authors.affiliation: Department of Physiological Sciences, Eastern Virginia School of Medicine, Norfolk, VA 23501, USA.
authors.forename: Souad
authors.initials: S
authors.lastname: Belmadani
authors.affiliation: Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, 1430 Tulane Ave, New Orleans, LA 70112, USA; Department of Physiological Sciences, Eastern Virginia School of Medicine, Norfolk, VA 23501, USA. Electronic address: matrouk@evms.edu.
authors.forename: Khalid
authors.initials: K
authors.lastname: Matrougui
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D020552:Comet Assay; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014415:Tunicamycin / Q000494:pharmacology; D014652:Vascular Diseases / Q000378:metabolism / Q000473:pathology*
chemical_list: D000998:Antiviral Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014415:Tunicamycin; D008156:Luciferases; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C060505:neutrophil cytosolic factor 1
keywords: Endoplasmic reticulum; Endothelial dysfunction; MAPKinase; Oxidative stress