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

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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 Ca 2+ -dependent cytosolic phospho- lipase A 2 (cPLA 2 ) 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 A 2 , PGF , and prostacyclin), 3) expression of COX-1, 4) phosphorylation of cPLA 2 and ERK1/2, and 5) production of H 2 O 2 . 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)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume305
Issue number3
DOIs
StatePublished - Aug 1 2013

Fingerprint

Endoplasmic Reticulum Stress
Inbred SHR Rats
Endothelium
Aorta
Prostaglandin-Endoperoxide Synthases
varespladib methyl
Lipase
Arachidonic Acid
Acetylcholine
Prostaglandins
Phosphorylation
Blood Pressure
tert-Butylhydroperoxide
Cyclooxygenase 1
Inbred WKY Rats
Thromboxanes
Mitogen-Activated Protein Kinase 1
Endothelins
Prostaglandins F
Epoprostenol

Keywords

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

ASJC Scopus subject areas

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

Cite this

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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 arachi- donic acid (AA) produced by Ca 2+ -dependent cytosolic phospho- lipase A 2 (cPLA 2 ) 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 A 2 , PGF 2α , and prostacyclin), 3) expression of COX-1, 4) phosphorylation of cPLA 2 and ERK1/2, and 5) production of H 2 O 2 . 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.",
keywords = "Cyclooxygenase, EDCF, ERK1/2, Endoplasmic reticulum stress, cPLA",
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N2 - 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 Ca 2+ -dependent cytosolic phospho- lipase A 2 (cPLA 2 ) 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 A 2 , PGF 2α , and prostacyclin), 3) expression of COX-1, 4) phosphorylation of cPLA 2 and ERK1/2, and 5) production of H 2 O 2 . 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.

AB - 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 Ca 2+ -dependent cytosolic phospho- lipase A 2 (cPLA 2 ) 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 A 2 , PGF 2α , and prostacyclin), 3) expression of COX-1, 4) phosphorylation of cPLA 2 and ERK1/2, and 5) production of H 2 O 2 . 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.

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