Autophagy protects HUVECs against ER stress-mediated apoptosis under simulated microgravity

Cheng-Fei Li,Yuan Gao,Yong-Chun Wang,Xi-Qing Sun,Fei Shi,Yi-Kai Pan

doi:10.1007/s10495-019-01560-w

Abstract

Astronauts exposed to a gravity-free environment experience cardiovascular deconditioning that causes post-spaceflight orthostatic intolerance and other pathological conditions. Endothelial dysfunction is an important factor responsible for this alteration. Our previous study showed enhanced autophagy in endothelial cells under simulated microgravity. The present study explored the cytoprotective role of autophagy under microgravity in human umbilical vein endothelial cells (HUVECs). We found that clinorotation for 48 h induced apoptosis and endoplasmic reticulum (ER) stress in HUVECs. ER stress and the unfolded protein response (UPR) partially contributed to apoptosis under clinorotation. Autophagy partially reduced ER stress and restored UPR signaling by autophagic clearance of ubiquitin-protein aggregates, thereby reducing apoptosis. In addition, the ER stress antagonist 4-phenylbutyric acid upregulated autophagy in HUVECs. Taken together, these findings indicate that autophagy plays a protective role against apoptosis under clinorotation by clearing protein aggregates and partially restoring the UPR.

Highlights

The cardiovascular consequences of exposure to microgravity are evident in the form of orthostatic intolerance, reduced aerobic exercise capacity, and hypovolemia
The increase in conversion of LC3I to LC3II and the increased light chain 3 (LC3) puncta represent autophagosome formation. Another useful marker for autophagic activity is p62, a polyubiquitin-binding protein that is degraded by autophagy; its decrease serves as an index of autophagic flux
These results indicated that 48 h clinorotation activated autophagy in human umbilical vein endothelial cells (HUVECs)

Summary

Introduction

The cardiovascular consequences of exposure to microgravity are evident in the form of orthostatic intolerance, reduced aerobic exercise capacity, and hypovolemia. Endothelial cells (ECs) form the inner layer of blood vessels, and their compromised function is hypothesized to be an important underlying mechanism of numerous cardiovascular diseases [1]. The vascular endothelium is highly sensitive to mechanical forces and undergoes significant morphological and functional changes at zero gravity via mechanotransduction processes [2], which are important causes of cardiovascular deconditioning following spaceflight. Autophagy is an essential process for cellular homeostasis by releasing energy substrates and eliminating defective or damaged organelles. It consists of sequestration of cytoplasmic organelles and proteins within an isolation membrane followed by selective degradation [3]. The role of autophagy in cell adaptation to microgravity is poorly understood

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