University of Surrey

Test tubes in the lab Research in the ATI Dance Research

Heme Oxygenase (HO)-1 Induction Prevents Endoplasmic Reticulum Stress-Mediated Endothelial Cell Death and Impaired Angiogenic Capacity

Maamoun, Hatem, Zachariah, Matshediso, McVey, John, Green, Fiona and Agouni, A (2016) Heme Oxygenase (HO)-1 Induction Prevents Endoplasmic Reticulum Stress-Mediated Endothelial Cell Death and Impaired Angiogenic Capacity Biochemical Pharmacology, 127. pp. 46-59.

[img] Text
Maamoun et al_Revised manuscript_30 11 16_UNmarked Version.docx - Accepted version Manuscript
Restricted to Repository staff only until 21 December 2017.
Available under License : See the attached licence file.

Download (2MB)
[img]
Preview
Text (licence)
SRI_deposit_agreement.pdf
Available under License : See the attached licence file.

Download (33kB) | Preview

Abstract

Most of diabetic cardiovascular complications are attributed to endothelial dysfunction and impaired angiogenesis. Endoplasmic Reticulum (ER) and oxidative stresses were shown to play a pivotal role in the development of endothelial dysfunction in diabetes. Hemeoxygenase-1 (HO-1) was shown to protect against oxidative stress in diabetes; however, its role in alleviating ER stress-induced endothelial dysfunction remains not fully elucidated. We aim here to test the protective role of HO-1 against high glucose-mediated ER stress and endothelial dysfunction and understand the underlying mechanisms with special emphasis on oxidative stress, inflammation and cell death. Human Umbilical Vein Endothelial Cells (HUVECs) were grown in either physiological or intermittent high concentrations of glucose for 5 days in the presence or absence of Cobalt (III) Protoporphyrin IX chloride (CoPP, HO-1 inducer) or 4-Phenyl Butyric Acid (PBA, ER stress inhibitor). Using an integrated cellular and molecular approach, we then assessed ER stress and inflammatory responses, in addition to apoptosis and angiogenic capacity in these cells. Our results show that HO-1 induction prevented high glucose-mediated increase of mRNA and protein expression of key ER stress markers. Cells incubated with high glucose exhibited high levels of oxidative stress, activation of major inflammatory and apoptotic responses [nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK)] and increased rate of apoptosis; however, cells pre-treated with CoPP or PBA were fully protected. In addition, high glucose enhanced caspases 3 and 7 cleavage and activity and augmented cleaved poly ADP ribose polymerase (PARP) expression whereas HO-1 induction prevented these effects. Finally, HO-1 induction and ER stress inhibition prevented high glucose-induced reduction in NO release and impaired the angiogenic capacity of HUVECs, and enhanced vascular endothelial growth factor (VEGF)-A expression. Altogether, we show here the critical role of ER stress-mediated cell death in diabetes-induced endothelial dysfunction and impaired angiogenesis and underscore the role of HO-1 induction as a key therapeutic modulator for ER stress response in ischemic disorders and diabetes. Our results also highlight the complex interplay between ER stress response and oxidative stress.

Item Type: Article
Subjects : Biosciences and Medicine
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Maamoun, Hatemh.maamoun@surrey.ac.ukUNSPECIFIED
Zachariah, Matshedisom.zachariah@surrey.ac.ukUNSPECIFIED
McVey, Johnj.mcvey@surrey.ac.ukUNSPECIFIED
Green, FionaF.Green@surrey.ac.ukUNSPECIFIED
Agouni, AUNSPECIFIEDUNSPECIFIED
Date : 21 December 2016
Identification Number : 10.1016/j.bcp.2016.12.009
Copyright Disclaimer : © 2016. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Uncontrolled Keywords : Endothelial dysfunction, ER stress, oxidative stress, Heme oxygenase-1
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 06 Jan 2017 09:22
Last Modified : 07 Jul 2017 11:06
URI: http://epubs.surrey.ac.uk/id/eprint/813210

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year


Information about this web site

© The University of Surrey, Guildford, Surrey, GU2 7XH, United Kingdom.
+44 (0)1483 300800