Endoplasmic reticulum stress inhibition blunts the development of essential hypertension in the spontaneously hypertensive rat

Abstract

Essential hypertension is the leading cause of premature death worldwide. However, hypertension’s cause remains uncertain. endoplasmic reticulum (ER) stress has recently been associated with hypertension, but it is unclear whether ER stress causes hypertension. To clarify this question, we examined if ER stress occurs in blood vessels before the development of hypertension and if ER stress inhibition would prevent hypertension development. We used the spontaneously hypertensive rat (SHR) as a model of human essential hypertension and the Wistar-Kyoto (WKY) rat as its normotensive control. Resistance arteries collected from young rats determined that ER stress was present in SHR vessels before the onset of hypertension. To assess the effect of ER stress inhibition on hypertension development, another subset of rats were treated with 4-phenylbutyric acid (4-PBA; 1 g·kg−1·day−1) for 8 wk from 5 wk of age. Blood pressure was measured via radiotelemetry and compared with untreated SHR and WKY rats. Mesenteric resistance arteries were collected and assessed for structural and functional changes associated with hypertension. Systolic and diastolic blood pressures were significantly lower in the 4-PBA-treated SHR groups than in untreated SHRs. Additionally, 4-PBA significantly decreased the media-to-lumen ratio and ER stress marker expression, improved vasodilatory response, and reduced contractile responses in resistance arteries from SHRs. Overall, ER stress inhibition blunted the development of hypertension in the SHR. These data add evidence to the hypothesis that a component of hypertension in the SHR is caused by ER stress. NEW & NOTEWORTHY In this study, 4-phenylbutyric acid’s (4-PBA’s) molecular chaperone capability was used to inhibit endoplasmic reticulum (ER) stress in the small arteries of young spontaneously hypertensive rats (SHRs) and reduce their hypertension. These effects are likely mediated through 4-PBA's effects to reduce resistant artery contractility and increase nitric oxide-mediated endothelial vasodilation through a process preventing endothelial dysfunction. Overall, ER stress inhibition blunted the development of hypertension in this young SHR model. This suggests that a component of the increase in blood pressure found in SHRs is due to ER stress. However, it is important to note that inhibition of ER stress was not able to fully restore the blood pressure to normal, suggesting that a component of hypertension may not be due to ER stress. This study points to the inhibition of ER stress as an important new physiological pathway to lower blood pressure, where other known approaches may not achieve blood pressure-lowering targets.

Rcn3 Suppression Was Responsible for Partial Relief of Emphysema as Shown by Specific Type II Alveolar Epithelial Cell Rcn3 CKO Mouse Model

“…Recently, it has been shown that ER stress was induced in mouse lungs in response to CS and the lungs of chronic smokers. 31 In our study, we observed the up-regulation of GRP78 in the lungs not only from COPD patients but also from two mouse models of emphysema. In the PPE-induced emphysema mice, the lung expressed less GRP78 when Rcn3 was deleted selectively in the AECIIs, which was in the same tendency with the changes of Rcn3 expression.…”

Profile and Functional Prediction of Plasma Exosome-Derived CircRNAs From Acute Ischemic Stroke Patients

“…According to GO annotations of host genes, the ribosome and ribonucleoprotein could be impacted in AIS, disordering RNA translation/regulation and protein processing in the endoplasmic reticulum, which was highlighted by KEGG analysis. It has been reported that endoplasmic reticulum stress induced by abnormal protein processing takes place in atherosclerosis ( Tabas, 2010 ; Huang et al, 2018 ) and hypertension ( Naiel et al, 2019 ; Liu et al, 2020 ), for which the underlying mechanism could be the dysfunction of vascular endothelial cells by endoplasmic reticulum stress, like excessive apoptosis ( Sun et al, 2015 ; Carlisle et al, 2016 ). Moreover, by KEGG pathway analysis, focal adhesion and leukocyte transendothelial migration were significantly enriched.…”

Chimonanthus salicifolius attenuated vascular remodeling by alleviating endoplasmic reticulum stress in spontaneously hypertensive rats

“…Excessive ER stress would lead to the upregulation of CHOP expression, which induces apoptosis. Previous studies have demonstrated that chronic high blood pressure increases ER stress, downregulates GRP78 expression, and upregulates CHOP in the cardiovascular systems of various models, such as angiotensin II-induced mice, 37 SHRs, 38 the deoxycorticosterone-acetate and salt-diet-induced rats 39 and aged mice. 40 Our study supported that ER stress induced apoptosis was involved in the pathogenesis of vascular remodeling in the aorta of SHRs.…”