期刊
JOURNAL OF HYPERTENSION
卷 34, 期 8, 页码 1556-1569出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/HJH.0000000000000943
关键词
4-phenylbutyric acid; endoplasmic reticulum stress; essential hypertension; nitric oxide; superoxide
资金
- Canadian Institutes of Health Research [OSO-115895, MOP-133484]
- St. Joseph's Healthcare Hamilton
- Father Sean O'Sullivan Research Centre at St. Joseph's Healthcare Hamilton
- McMaster University, Department of Medicine
- division of Nephrology in the Department of Medicine at McMaster University
- Kidney foundation of Canada
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.
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