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

Erscheinungsjahr:

2016

Erschienen:

2016

Enthalten in:

Zur Gesamtaufnahme - volume:34

Enthalten in:

Journal of hypertension - 34(2016), 8 vom: 15. Aug., Seite 1556-69

Sprache:

Englisch

Beteiligte Personen:

Carlisle, Rachel E [VerfasserIn]
Werner, Kaitlyn E [VerfasserIn]
Yum, Victoria [VerfasserIn]
Lu, Chao [VerfasserIn]
Tat, Victor [VerfasserIn]
Memon, Muzammil [VerfasserIn]
No, Yejin [VerfasserIn]
Ask, Kjetil [VerfasserIn]
Dickhout, Jeffrey G [VerfasserIn]

Links:

Volltext

Themen:

11089-65-9
4-phenylbutyric acid
7WY7YBI87E
Journal Article
Phenylbutyrates
Reactive Oxygen Species
Tunicamycin

Anmerkungen:

Date Completed 12.09.2017

Date Revised 02.12.2018

published: Print

Citation Status MEDLINE

doi:

10.1097/HJH.0000000000000943

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM259746134