title: Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity.
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 5days 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.
authors.affiliation: University of Surrey, Faculty of Health and Medical Sciences, School of Biosciences & Medicine, Guildford GU2 7XH, United Kingdom.
authors.forename: Hatem
authors.initials: H
authors.lastname: Maamoun
authors.affiliation: University of Surrey, Faculty of Health and Medical Sciences, School of Biosciences & Medicine, Guildford GU2 7XH, United Kingdom.
authors.forename: Matshediso
authors.initials: M
authors.lastname: Zachariah
authors.affiliation: University of Surrey, Faculty of Health and Medical Sciences, School of Biosciences & Medicine, Guildford GU2 7XH, United Kingdom.
authors.forename: John H
authors.initials: JH
authors.lastname: McVey
authors.affiliation: University of Surrey, Faculty of Health and Medical Sciences, School of Biosciences & Medicine, Guildford GU2 7XH, United Kingdom.
authors.forename: Fiona R
authors.initials: FR
authors.lastname: Green
authors.affiliation: Qatar University, College of Pharmacy, Pharmaceutical Sciences Section, P.O. Box 2713, Doha, Qatar. Electronic address: aagouni@qu.edu.qa.
authors.forename: Abdelali
authors.initials: A
authors.lastname: Agouni
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D016923:Cell Death; D059865:Endoplasmic Reticulum Stress; D004790:Enzyme Induction; D005947:Glucose / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D011524:Protoporphyrins / Q000494:pharmacology
chemical_list: D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1; D053148:Caspase 3; D053179:Caspase 7; D005947:Glucose
keywords: 4-Phenyl Butyric Acid (PBA, PubChem CID:4775); Cobalt (III) Protoporphyrin IX chloride (CoPP, PubChem CID:9961203); ER stress; Endothelial dysfunction; Heme oxygenase-1; Oxidative stress; Sn Protoporphyrin IX dichloride (SnPP, PubChem CID: 73755113)