Suppression of endoplasmic reticulum stress improves endothelium-dependent contractile responses in aorta of the spontaneously hypertensive rat

Kathryn M. Spitler, Takayuki Matsumoto, R Clinton Webb

Research output: Contribution to journalArticle

57 Scopus citations

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 arachi- donic acid (AA) produced by Ca2+-dependent cytosolic phospho- lipase A2 (cPLA2) following phosphorylation (at Ser505) 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, PGF, 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.

Original languageEnglish (US)
Pages (from-to)H344-H353
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume305
Issue number3
DOIs
StatePublished - Aug 1 2013

Keywords

  • Cyclooxygenase
  • EDCF
  • ERK1/2
  • Endoplasmic reticulum stress
  • cPLA

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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