title: Suppression of endoplasmic reticulum stress improves endothelium-dependent contractile responses in aorta of the spontaneously hypertensive rat.
abstract: A contributing factor to increased peripheral resistance seen during hypertension is an increased production of endothelium-derived contractile factors (EDCFs). The main EDCFs are vasoconstrictor prostanoids, metabolites of arachidonic acid (AA) produced by Ca(2+)-dependent cytosolic phospholipase A2 (cPLA2) following phosphorylation (at Ser(505)) mediated by extracellular signal-regulated kinase (ERK1/2) and cyclooxygenase (COX) activations. Although endoplasmic reticulum (ER) stress has been shown to contribute to pathophysiological alterations in cardiovascular diseases, the relationship between ER stress and EDCF-mediated responses remains unclear. We tested the hypothesis that ER stress plays a role in EDCF-mediated responses via activation of the cPLA2/COX pathway in the aorta of the spontaneously hypertensive rat (SHR). Male SHR and Wistar-Kyoto rats (WKY) were treated with ER stress inhibitor, tauroursodeoxycholic acid or 4-phenlybutyric acid (TUDCA or PBA, respectively, 100 mg·kg(-1)·day(-1) ip) or PBS (control, 300 μl/day ip) for 1 wk. There was a decrease in systolic blood pressure in SHR treated with TUDCA or PBA compared with control SHR (176 ± 3 or 181 ± 5, respectively vs. 200 ± 2 mmHg). In the SHR, treatment with TUDCA or PBA normalized aortic (vs. control SHR) 1) contractions to acetylcholine (ACh), AA, and tert-butyl hydroperoxide, 2) ACh-stimulated releases of prostanoids (thromboxane A2, PGF2α, and prostacyclin), 3) expression of COX-1, 4) phosphorylation of cPLA2 and ERK1/2, and 5) production of H2O2. Our findings demonstrate a novel interplay between ER stress and EDCF-mediated responses in the aorta of the SHR. Moreover, ER stress inhibition normalizes such responses by suppressing the cPLA2/COX pathway.
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, GA 30912, USA. kmspitler@gmail.com
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Spitler
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D016718:Arachidonic Acid / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000378:metabolism; D015237:Dinoprost / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D011464:Epoprostenol / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology*; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; C494828:Bax protein, rat; D008565:Membrane Proteins; D010654:Phenylbutyrates; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D051028:bcl-2-Associated X Protein; D016718:Arachidonic Acid; D013655:Taurochenodeoxycholic Acid; D013928:Thromboxane A2; C031655:ursodoxicoltaurine; C075773:4-phenylbutyric acid; D020122:tert-Butylhydroperoxide; D015237:Dinoprost; D006861:Hydrogen Peroxide; D011464:Epoprostenol; D051545:Cyclooxygenase 1; C496513:Ptgs1 protein, rat; C535149:Mapk1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054510:Phospholipases A2, Cytosolic; D000109:Acetylcholine
keywords: EDCF; ERK1/2; cPLA2; cyclooxygenase; endoplasmic reticulum stress