Exercise ameliorates endoplasmic reticulum stress-mediated vascular dysfunction in mesenteric arteries in atherosclerosis

Junyoung Hong,Sean P. Marrelli,Kwangchan Kim,Yoonjung Park,Eunkyung Park,Jonghae Lee,Melissa M. Markofski

doi:10.1038/s41598-018-26188-9

Junyoung Hong, Sean P. Marrelli + Show 5 more

Open Access

https://doi.org/10.1038/s41598-018-26188-9

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Abstract

Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis, but the effects of exercise on ER stress-mediated endothelial dysfunction in atherosclerosis is not yet fully understood. We assessed endothelium-dependent vasodilation in isolated mesenteric arteries from wild type (WT), WT with exercise (WT-EX), ApoE knockout (ApoE KO), and ApoE KO mice with exercise (ApoE KO-EX). Vasodilation to acetylcholine (ACh) was elicited in the presence of inhibitors of ER stress, eNOS, caspase-1, and UCP-2 (Tudca, L-NAME, AC-YVARD-cmk, and Genipin, respectively) and the ER stress inducer (Tunicamycin). Immunofluorescence was used to visualize the expression of CHOP, as an indicator of ER stress, in superior mesenteric arteries (SMA). Dilation to ACh was attenuated in ApoE KO but was improved in ApoE KO-EX. Incubation of Tudca and AC-YVARD-cmk improved ACh-induced vasodilation in ApoE KO. L-NAME, tunicamycin, and Genipin attenuated vasodilation in WT, WT-EX and ApoE KO-EX, but not in ApoE KO. Exercise training reversed the increase in CHOP expression in the endothelium of SMA of ApoE KO mice. We conclude that ER stress plays a significant role in endothelial dysfunction of resistance arteries in atherosclerosis and that exercise attenuates ER stress and regulates its critical downstream signaling pathways including eNOS, UCP-2 and caspase-1.

Highlights

The endoplasmic reticulum (ER) is an organelle that modulates various physiological processes including protein folding, calcium homeostasis, and lipid biosynthesis for maintaining cellular homeostasis
The present findings show the contribution of Endoplasmic reticulum (ER) stress to the endothelial dysfunction and the effects of exercise training to reverse ER stress-mediated vascular dysfunction in mesenteric arteries of ApoE knockout (ApoE KO) mice
The key findings are as follows: 1) Exercise training normalized heart/body weight ratio and atherosclerotic region in ApoE KO mice; 2) ACh-induced endothelium-dependent vasodilation was impaired in mesenteric arteries of ApoE KO mice and was ameliorated by exercise training through restored endothelial NO signaling; and 3) The changes mediated by ER stress were associated with caspase-1 and Uncoupling protein-2 (UCP-2)

Summary

Introduction

The endoplasmic reticulum (ER) is an organelle that modulates various physiological processes including protein folding, calcium homeostasis, and lipid biosynthesis for maintaining cellular homeostasis. Multiple pathologic factors, such as hyperlipidemia, oxidative stress, and calcium imbalance trigger prolonged disturbances or perturbations on ER homeostasis, leading to the unfolded protein response (UPR) pathway in the ER lumen which is known as ER stress. The direct effects of exercise on ER stress-mediated endothelial dysfunction and on ER stress-associated caspase-1 and UCP-2 signaling in atherosclerosis merit further examination. Our study focuses on endothelial function of mesenteric arteries to determine whether atherosclerosis impairs endothelial function in resistance vessels which are central in blood pressure regulation

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