Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=28134810
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human
Vascular Endothelial Cells
#MMPMID28134810
Dong L
; Krewson EA
; Yang LV
Int J Mol Sci
2017[Jan]; 18
(2
): ? PMID28134810
show ga
Acidosis commonly exists in the tissue microenvironment of various
pathophysiological conditions such as tumors, inflammation, ischemia, metabolic
disease, and respiratory disease. For instance, the tumor microenvironment is
characterized by acidosis and hypoxia due to tumor heterogeneity, aerobic
glycolysis (the "Warburg effect"), and the defective vasculature that cannot
efficiently deliver oxygen and nutrients or remove metabolic acid byproduct. How
the acidic microenvironment affects the function of blood vessels, however, is
not well defined. GPR4 (G protein-coupled receptor 4) is a member of the
proton-sensing G protein-coupled receptors and it has high expression in
endothelial cells (ECs). We have previously reported that acidosis induces a
broad inflammatory response in ECs. Acidosis also increases the expression of
several endoplasmic reticulum (ER) stress response genes such as CHOP (C/EBP
homologous protein) and ATF3 (activating transcription factor 3). In the current
study, we have examined acidosis/GPR4- induced ER stress pathways in human
umbilical vein endothelial cells (HUVEC) and other types of ECs. All three arms
of the ER stress/unfolded protein response (UPR) pathways were activated by
acidosis in ECs as an increased expression of phosphorylated eIF2? (eukaryotic
initiation factor 2?), phosphorylated IRE1? (inositol-requiring enzyme 1?), and
cleaved ATF6 upon acidic pH treatment was observed. The expression of other
downstream mediators of the UPR, such as ATF4, ATF3, and spliced XBP-1 (X
box-binding protein 1), was also induced by acidosis. Through genetic and
pharmacological approaches to modulate the expression level or activity of GPR4
in HUVEC, we found that GPR4 plays an important role in mediating the ER stress
response induced by acidosis. As ER stress/UPR can cause inflammation and cell
apoptosis, acidosis/GPR4-induced ER stress pathways in ECs may regulate vascular
growth and inflammatory response in the acidic microenvironment.
free
free
free
