Endoplasmic reticulum stress inhibition reduces hypertension through the preservation of resistance blood vessel structure and function
OBJECTIVE: Our purpose was to determine if endoplasmic reticulum stress inhibition lowers blood pressure (BP) in hypertension by correcting vascular dysfunction.
METHODS: The spontaneously hypertensive rat (SHR) was used as a model of human essential hypertension with its normotensive control, the Wistar Kyoto rat. Animals were subjected to endoplasmic reticulum stress inhibition with 4-phenylbutyric acid (4-PBA; 1 g/kg per day, orally) for 5 weeks from 12 weeks of age. BP was measured weekly noninvasively and at endpoint with carotid arterial cannulation. Small mesenteric arteries were removed for vascular studies. Function was assessed with a Mulvany-Halpern style myograph, and structure was assessed by measurement of medial-to-lumen ratio in perfusion fixed vessels as well as three-dimensional confocal reconstruction of vessel wall components. Endoplasmic reticulum stress was assessed by quantitative real time-PCR and western blotting; oxidative stress was assessed by 3-nitrotyrosine and dihydroethidium staining.
RESULTS: 4-PBA significantly lowered BP in SHR (vehicle 206.1 ± 4.3 vs. 4-PBA 178.9 ± 3.1, systolic) but not Wistar Kyoto. 4-PBA diminished contractility and augmented endothelial-dependent vasodilation in SHR small mesenteric arteries, as well as reducing media-to-lumen ratio. 4-PBA significantly reduced endoplasmic reticulum stress in SHR resistance vessels. Normotensive resistance vessels, treated with the endoplasmic reticulum stress-inducing agent, tunicamycin, show decreased endothelial-dependent vasodilation; this was improved with 4-PBA treatment. 3-Nitrotyrosine and dihydroethidium staining indicated that endoplasmic reticulum stress leads to reactive oxygen species generation resolvable by 4-PBA treatment.
CONCLUSION: Endoplasmic reticulum stress caused endothelial-mediated vascular dysfunction contributing to elevated BP in the SHR model of human essential hypertension.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2016 |
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Erschienen: |
2016 |
Enthalten in: |
Zur Gesamtaufnahme - volume:34 |
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Enthalten in: |
Journal of hypertension - 34(2016), 8 vom: 15. Aug., Seite 1556-69 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Carlisle, Rachel E [VerfasserIn] |
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Links: |
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Themen: |
11089-65-9 |
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Anmerkungen: |
Date Completed 12.09.2017 Date Revised 02.12.2018 published: Print Citation Status MEDLINE |
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doi: |
10.1097/HJH.0000000000000943 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM259746134 |
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100 | 1 | |a Carlisle, Rachel E |e verfasserin |4 aut | |
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500 | |a published: Print | ||
500 | |a Citation Status MEDLINE | ||
520 | |a OBJECTIVE: Our purpose was to determine if endoplasmic reticulum stress inhibition lowers blood pressure (BP) in hypertension by correcting vascular dysfunction | ||
520 | |a METHODS: The spontaneously hypertensive rat (SHR) was used as a model of human essential hypertension with its normotensive control, the Wistar Kyoto rat. Animals were subjected to endoplasmic reticulum stress inhibition with 4-phenylbutyric acid (4-PBA; 1 g/kg per day, orally) for 5 weeks from 12 weeks of age. BP was measured weekly noninvasively and at endpoint with carotid arterial cannulation. Small mesenteric arteries were removed for vascular studies. Function was assessed with a Mulvany-Halpern style myograph, and structure was assessed by measurement of medial-to-lumen ratio in perfusion fixed vessels as well as three-dimensional confocal reconstruction of vessel wall components. Endoplasmic reticulum stress was assessed by quantitative real time-PCR and western blotting; oxidative stress was assessed by 3-nitrotyrosine and dihydroethidium staining | ||
520 | |a RESULTS: 4-PBA significantly lowered BP in SHR (vehicle 206.1 ± 4.3 vs. 4-PBA 178.9 ± 3.1, systolic) but not Wistar Kyoto. 4-PBA diminished contractility and augmented endothelial-dependent vasodilation in SHR small mesenteric arteries, as well as reducing media-to-lumen ratio. 4-PBA significantly reduced endoplasmic reticulum stress in SHR resistance vessels. Normotensive resistance vessels, treated with the endoplasmic reticulum stress-inducing agent, tunicamycin, show decreased endothelial-dependent vasodilation; this was improved with 4-PBA treatment. 3-Nitrotyrosine and dihydroethidium staining indicated that endoplasmic reticulum stress leads to reactive oxygen species generation resolvable by 4-PBA treatment | ||
520 | |a CONCLUSION: Endoplasmic reticulum stress caused endothelial-mediated vascular dysfunction contributing to elevated BP in the SHR model of human essential hypertension | ||
650 | 4 | |a Journal Article | |
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700 | 1 | |a Werner, Kaitlyn E |e verfasserin |4 aut | |
700 | 1 | |a Yum, Victoria |e verfasserin |4 aut | |
700 | 1 | |a Lu, Chao |e verfasserin |4 aut | |
700 | 1 | |a Tat, Victor |e verfasserin |4 aut | |
700 | 1 | |a Memon, Muzammil |e verfasserin |4 aut | |
700 | 1 | |a No, Yejin |e verfasserin |4 aut | |
700 | 1 | |a Ask, Kjetil |e verfasserin |4 aut | |
700 | 1 | |a Dickhout, Jeffrey G |e verfasserin |4 aut | |
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