{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:23:52Z","timestamp":1790036632251,"version":"4.0.1"},"reference-count":176,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2019,7,26]],"date-time":"2019-07-26T00:00:00Z","timestamp":1564099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003825","name":"Magyar Tudom\u00e1nyos Akad\u00e9mia","doi-asserted-by":"publisher","award":["11003"],"award-info":[{"award-number":["11003"]}],"id":[{"id":"10.13039\/501100003825","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hungarian Government grants","award":["OTKA-K112333 (J.B.)"],"award-info":[{"award-number":["OTKA-K112333 (J.B.)"]}]},{"name":"The European Union and the European Social Fund","award":["GINOP-2.3.2-15-2016-00043 (IRONHEARTH)"],"award-info":[{"award-number":["GINOP-2.3.2-15-2016-00043 (IRONHEARTH)"]}]},{"name":"The European Union and the European Social Fund","award":["EFOP-3.6.2-16-2017-00006 (LIVE LONGER)"],"award-info":[{"award-number":["EFOP-3.6.2-16-2017-00006 (LIVE LONGER)"]}]},{"name":"Thematic Excellence Programme of the Ministry for Innovation and Technology in Hungary","award":["Space Sciences thematic programme of the University of Debrecen"],"award-info":[{"award-number":["Space Sciences thematic programme of the University of Debrecen"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The prevalence of vascular disorders continues to rise worldwide. Parallel with that, new pathophysiological pathways have been discovered, providing possible remedies for prevention and therapy in vascular diseases. Growing evidence suggests that endoplasmic reticulum (ER) stress is involved in a number of vasculopathies, including atherosclerosis, vascular brain events, and diabetes. Heme, which is released from hemoglobin or other heme proteins, triggers various pathophysiological consequence, including heme stress as well as ER stress. The potentially toxic free heme is converted by heme oxygenases (HOs) into carbon monoxide (CO), iron, and biliverdin (BV), the latter of which is reduced to bilirubin (BR). Redox-active iron is oxidized and stored by ferritin, an iron sequestering protein which exhibits ferroxidase activity. In recent years, CO, BV, and BR have been shown to control cellular processes such as inflammation, apoptosis, and antioxidant defense. This review covers our current knowledge about how heme induced endoplasmic reticulum stress (HIERS) participates in the pathogenesis of vascular disorders and highlights recent discoveries in the molecular mechanisms of HO-mediated cytoprotection in heme stress and ER stress, as well as crosstalk between ER stress and HO-1. Furthermore, we focus on the translational potential of HIERS and heme oxygenase-1 (HO-1) in atherosclerosis, diabetes mellitus, and brain hemorrhage.<\/jats:p>","DOI":"10.3390\/ijms20153675","type":"journal-article","created":{"date-parts":[[2019,7,26]],"date-time":"2019-07-26T11:55:22Z","timestamp":1564142122000},"page":"3675","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Heme, Heme Oxygenase, and Endoplasmic Reticulum Stress\u2014A New Insight into the Pathophysiology of Vascular Diseases"],"prefix":"10.3390","volume":"20","author":[{"given":"Tam\u00e1s","family":"G\u00e1ll","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gy\u00f6rgy","family":"Balla","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7923-2645","authenticated-orcid":false,"given":"J\u00f3zsef","family":"Balla","sequence":"additional","affiliation":[{"name":"HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, 4032 Debrecen, Hungary"},{"name":"Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/S0021-9258(18)93628-8","article-title":"Exchange of heme among hemoglobins and between hemoglobin and albumin","volume":"243","author":"Bunn","year":"1968","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18148","DOI":"10.1016\/S0021-9258(19)37165-0","article-title":"Ferritin: A cytoprotective antioxidant strategem of endothelium","volume":"267","author":"Balla","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_3","first-page":"841","article-title":"Antioxidant activities of bile pigments","volume":"6","author":"Stocker","year":"2004","journal-title":"Antioxid. Redox Signal."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1038\/nrd3228","article-title":"The therapeutic potential of carbon monoxide","volume":"9","author":"Motterlini","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1146\/annurev.pharmtox.37.1.517","article-title":"The heme oxygenase system: a regulator of second messenger gases","volume":"37","author":"Maines","year":"1997","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Tenhunen, R., Marver, H.S., and Schmid, R. (1968). The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc. Natl. Acad. Sci., 61.","DOI":"10.1073\/pnas.61.2.748"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1089\/ars.2013.5675","article-title":"New insights into intracellular locations and functions of heme oxygenase-1","volume":"20","author":"Dunn","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1152\/physrev.00011.2005","article-title":"Heme oxygenase-1\/carbon monoxide: from basic science to therapeutic applications","volume":"86","author":"Ryter","year":"2006","journal-title":"Physiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1111\/j.1432-1033.1990.tb19263.x","article-title":"Regulation of heme oxygenase gene expression by cobalt in rat liver and kidney","volume":"192","author":"Lin","year":"1990","journal-title":"Eur. J. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1073\/pnas.84.8.2464","article-title":"Dual control mechanism for heme oxygenase: tin(IV)-protoporphyrin potently inhibits enzyme activity while markedly increasing content of enzyme protein in liver","volume":"84","author":"Sardana","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3136","DOI":"10.1111\/j.1742-4658.2006.05319.x","article-title":"Hypoxia reduces the expression of heme oxygenase-2 in various types of human cell lines. A possible strategy for the maintenance of intracellular heme level","volume":"273","author":"Zhang","year":"2006","journal-title":"FEBS J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/j.neuroscience.2008.07.004","article-title":"Heme oxygenase 2 deficiency increases brain swelling and inflammation after intracerebral hemorrhage","volume":"155","author":"Wang","year":"2008","journal-title":"Neuroscience"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1007\/BF03401984","article-title":"Heme oxygenase-2 is neuroprotective in cerebral ischemia","volume":"5","author":"Sampei","year":"1999","journal-title":"Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1210\/er.2007-0015","article-title":"The role for endoplasmic reticulum stress in diabetes mellitus","volume":"29","author":"Eizirik","year":"2008","journal-title":"Endocr. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10495-016-1296-4","article-title":"The role of endoplasmic reticulum stress in neurodegenerative disease","volume":"22","author":"Xiang","year":"2017","journal-title":"Apoptosis"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/nrrheum.2016.192","article-title":"Causes and consequences of endoplasmic reticulum stress in rheumatic disease","volume":"13","author":"Navid","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"170018","DOI":"10.1183\/16000617.0018-2017","article-title":"Endoplasmic reticulum stress in lung disease","volume":"26","author":"Marciniak","year":"2017","journal-title":"Eur. Respir. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ivanova, E.A., and Orekhov, A.N. (2016). The Role of Endoplasmic Reticulum Stress and Unfolded Protein Response in Atherosclerosis. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17020193"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/0014-4886(79)90080-3","article-title":"V Focal epileptogenesis after intracortical hemoglobin injection","volume":"66","author":"Rosen","year":"1979","journal-title":"Exp. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1172\/JCI112865","article-title":"Hemoglobin potentiates central nervous system damage","volume":"79","author":"Sadrzadeh","year":"1987","journal-title":"J. Clin. Invest."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1126\/science.7027441","article-title":"Hemin lyses malaria parasites","volume":"214","author":"Orjih","year":"1981","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"981","DOI":"10.2174\/0929867043455521","article-title":"Biology of heme in health and disease","volume":"11","author":"Wijayanti","year":"2004","journal-title":"Curr. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/S0021-9258(18)65938-1","article-title":"Unsaturated lipide oxidation catalyzed by hematin compounds","volume":"217","author":"TAPPEL","year":"1955","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1042\/bj2560861","article-title":"Antioxidant protection by haemopexin of haem-stimulated lipid peroxidation","volume":"256","author":"Gutteridge","year":"1988","journal-title":"Biochem. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1006\/abbi.1993.1566","article-title":"Hemin-induced lipid membrane disorder and increased permeability: a molecular model for the mechanism of cell lysis","volume":"307","author":"Schmitt","year":"1993","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"12069","DOI":"10.1016\/S0021-9258(17)44341-9","article-title":"Hemin-mediated DNA strand scission","volume":"258","author":"Aft","year":"1983","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/S0891-5849(01)00797-3","article-title":"Rapid mtDNA deletion by oxidants in rat liver mitochondria after hemin exposure","volume":"32","author":"Suliman","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0021-9258(17)43657-X","article-title":"Hemin-mediated oxidative degradation of proteins","volume":"259","author":"Aft","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.3389\/fphys.2018.01595","article-title":"Heme Induces Endoplasmic Reticulum Stress (HIER Stress) in Human Aortic Smooth Muscle Cells","volume":"9","author":"Nagy","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"29582","DOI":"10.1074\/jbc.M109.045344","article-title":"Oxidized hemoglobin is an endogenous proinflammatory agonist that targets vascular endothelial cells","volume":"284","author":"Silva","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1182\/blood.V98.6.1802","article-title":"Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase","volume":"98","author":"Wagener","year":"2001","journal-title":"Blood"},{"key":"ref_32","first-page":"648","article-title":"Exposure of endothelial cells to free heme potentiates damage mediated by granulocytes and toxic oxygen species","volume":"64","author":"Balla","year":"1991","journal-title":"Lab. Invest."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.1182\/blood-2011-08-375303","article-title":"Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production","volume":"119","author":"Fortes","year":"2012","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1097\/00041433-199710000-00005","article-title":"Mechanisms of oxidative damage of low density lipoprotein in human atherosclerosis","volume":"8","author":"Heinecke","year":"1997","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"16023","DOI":"10.1074\/jbc.275.21.16023","article-title":"Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages","volume":"275","author":"Ishii","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S0076-6879(04)78021-0","article-title":"Unique function of the Nrf2-Keap1 pathway in the inducible expression of antioxidant and detoxifying enzymes","volume":"378","author":"Kobayashi","year":"2004","journal-title":"Methods Enzymol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1161\/CIRCRESAHA.110.231985","article-title":"Interplay between heme oxygenase-1 and the multifunctional transcription factor yin yang 1 in the inhibition of intimal hyperplasia","volume":"107","author":"Beck","year":"2010","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1165\/ajrcmb.13.4.7546768","article-title":"Induction of heme oxygenase-1 gene expression by lipopolysaccharide is mediated by AP-1 activation","volume":"13","author":"Camhi","year":"1995","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_39","first-page":"924","article-title":"Regulation of Heme Oxygenase-1 Gene Transcription: Recent Advances and Highlights from the International Conference (Uppsala, 2003) on Heme Oxygenase","volume":"6","author":"Alam","year":"2004","journal-title":"Antioxid. Redox Signal."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5375","DOI":"10.1074\/jbc.272.9.5375","article-title":"Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia","volume":"272","author":"Lee","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science (80-. )."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5493","DOI":"10.1091\/mbc.e05-03-0268","article-title":"PERK and GCN2 Contribute to eIF2 Phosphorylation and Cell Cycle Arrest after Activation of the Unfolded Protein Response Pathway","volume":"16","author":"Hamanaka","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.biocel.2007.01.020","article-title":"Activating transcription factor 4","volume":"40","author":"Ameri","year":"2008","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1101\/gad.12.7.982","article-title":"CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum","volume":"12","author":"Zinszner","year":"1998","journal-title":"Genes Dev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/sj.cdd.4401373","article-title":"Roles of CHOP\/GADD153 in endoplasmic reticulum stress","volume":"11","author":"Oyadomari","year":"2004","journal-title":"Cell Death Differ."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1038\/nrd2755","article-title":"Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities","volume":"7","author":"Kim","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6245","DOI":"10.4049\/jimmunol.176.10.6245","article-title":"C\/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation","volume":"176","author":"Endo","year":"2006","journal-title":"J. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/ncb0311-184","article-title":"Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress","volume":"13","author":"Tabas","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3727\/105221610X12819686555051","article-title":"Emerging roles for XBP1, a sUPeR transcription factor","volume":"15","author":"He","year":"2010","journal-title":"Gene Expr."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1101\/gad.992302","article-title":"ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats","volume":"16","author":"Nishitoh","year":"2002","journal-title":"Genes Dev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/nri2359","article-title":"The endoplasmic reticulum stress response in immunity and autoimmunity","volume":"8","author":"Todd","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7198","DOI":"10.1128\/MCB.23.20.7198-7209.2003","article-title":"Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival","volume":"23","author":"Cullinan","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1161\/CIRCRESAHA.107.154781","article-title":"Carbon Monoxide Induces Heme Oxygenase-1 via Activation of Protein Kinase R\u2013Like Endoplasmic Reticulum Kinase and Inhibits Endothelial Cell Apoptosis Triggered by Endoplasmic Reticulum Stress","volume":"101","author":"Kim","year":"2007","journal-title":"Circ. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"20858","DOI":"10.1074\/jbc.M101198200","article-title":"Identification of Activating Transcription Factor 4 (ATF4) as an Nrf2-interacting Protein","volume":"276","author":"He","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2592","DOI":"10.1172\/JCI78031","article-title":"ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis","volume":"125","author":"Dey","year":"2015","journal-title":"J. Clin. Invest."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1016\/j.bbamcr.2012.06.001","article-title":"Implication of Nrf2 and ATF4 in differential induction of CHOP by proteasome inhibition in thyroid cancer cells","volume":"1823","author":"Zong","year":"2012","journal-title":"Biochim. Biophys. Acta - Mol. Cell Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.molcel.2016.07.019","article-title":"Cysteine Sulfenylation Directs IRE-1 to Activate the SKN-1\/Nrf2 Antioxidant Response","volume":"63","author":"Hourihan","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"20108","DOI":"10.1074\/jbc.M314219200","article-title":"PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress","volume":"279","author":"Cullinan","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1096\/fj.06-6114com","article-title":"Cytocidal effects of atheromatous plaque components: the death zone revisited","volume":"20","author":"Li","year":"2006","journal-title":"FASEB J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1161\/ATVBAHA.110.206433","article-title":"Red Cells, Hemoglobin, Heme, Iron, and Atherogenesis","volume":"30","author":"Nagy","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9285","DOI":"10.1073\/pnas.90.20.9285","article-title":"Endothelial-cell heme uptake from heme proteins: induction of sensitization and desensitization to oxidant damage","volume":"90","author":"Balla","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1182\/blood.V100.3.879","article-title":"Pro-oxidant and cytotoxic effects of circulating heme","volume":"100","author":"Jeney","year":"2002","journal-title":"Blood"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1161\/01.ATV.11.6.1700","article-title":"Hemin: A possible physiological mediator of low density lipoprotein oxidation and endothelial injury","volume":"11","author":"Balla","year":"1991","journal-title":"Arterioscler. Thromb. J. Vasc. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"676425","DOI":"10.1155\/2013\/676425","article-title":"Atherogenesis may involve the prooxidant and proinflammatory effects of ferryl hemoglobin","volume":"2013","author":"Potor","year":"2013","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.ijcard.2011.12.068","article-title":"Erythrocytes from patients with carotid atherosclerosis fail to control dendritic cell maturation","volume":"155","author":"Buttari","year":"2012","journal-title":"Int. J. Cardiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1160\/TH11-02-0110","article-title":"Redox imbalance of red blood cells impacts T lymphocyte homeostasis: implication in carotid atherosclerosis","volume":"106","author":"Profumo","year":"2011","journal-title":"Thromb. Haemost."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/0891-5849(88)90070-6","article-title":"Lipid peroxidation and endothelial cell injury: implications in atherosclerosis","volume":"4","author":"Hennig","year":"1988","journal-title":"Free Radic. Biol. Med."},{"key":"ref_68","first-page":"915","article-title":"Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity","volume":"320","author":"Steinberg","year":"1989","journal-title":"N. Engl. J. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1172\/JCI115499","article-title":"Role of oxidized low density lipoprotein in atherogenesis","volume":"88","author":"Witztum","year":"1991","journal-title":"J. Clin. Invest."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/S0022-2275(20)40739-4","article-title":"Lethal damage to endothelial cells by oxidized low density lipoprotein: role of selenoperoxidases in cytoprotection against lipid hydroperoxide- and iron-mediated reactions","volume":"34","author":"Thomas","year":"1993","journal-title":"J. Lipid Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0021-9150(95)05610-6","article-title":"V Toxicity of oxidized low density lipoproteins for vascular smooth muscle cells and partial protection by antioxidants","volume":"118","author":"Guyton","year":"1995","journal-title":"Atherosclerosis"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/0014-5793(94)01393-F","article-title":"Oxidized low-density lipoprotein is cytotoxic to human monocyte-macrophages: protection with lipophilic antioxidants","volume":"358","author":"Marchant","year":"1995","journal-title":"FEBS Lett."},{"key":"ref_73","first-page":"F814","article-title":"Renal tubular epithelial cells mimic endothelial cells upon exposure to oxidized LDL","volume":"271","author":"Agarwal","year":"1996","journal-title":"Am. J. Physiol."},{"key":"ref_74","first-page":"711","article-title":"Expression of heme oxygenase-1 in atherosclerotic lesions","volume":"152","author":"Wang","year":"1998","journal-title":"Am. J. Pathol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1172\/JCI4165","article-title":"Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency","volume":"103","author":"Yachie","year":"1999","journal-title":"J. Clin. Invest."},{"key":"ref_76","first-page":"377","article-title":"Oxidation of hemoglobin by lipid hydroperoxide associated with low-density lipoprotein (LDL) and increased cytotoxic effect by LDL oxidation in heme oxygenase-1 (HO-1) deficiency","volume":"51","author":"Nagy","year":"2005","journal-title":"Cell. Mol. Biol. (Noisy-le-grand)"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.1161\/CIRCULATIONAHA.108.808618","article-title":"Heme oxygenase 1 determines atherosclerotic lesion progression into a vulnerable plaque","volume":"119","author":"Cheng","year":"2009","journal-title":"Circulation"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1161\/STROKEAHA.118.022256","article-title":"Plasma Heme Oxygenase-1 Levels and Carotid Atherosclerosis","volume":"49","author":"Kishimoto","year":"2018","journal-title":"Stroke"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1159\/000492257","article-title":"Zedoarondiol Attenuates Endothelial Cells Injury Induced by Oxidized Low-Density Lipoprotein via Nrf2 Activation","volume":"48","author":"Mao","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.yexcr.2017.02.040","article-title":"Atractylenolide I restores HO-1 expression and inhibits Ox-LDL-induced VSMCs proliferation, migration and inflammatory responses in vitro","volume":"353","author":"Li","year":"2017","journal-title":"Exp. Cell Res."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Vogel, M.E., Idelman, G., Konaniah, E.S., and Zucker, S.D. (2017). Bilirubin Prevents Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice by Inhibiting Endothelial VCAM-1 and ICAM-1 Signaling. J. Am. Heart Assoc., 6.","DOI":"10.1161\/JAHA.116.004820"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s10238-017-0470-5","article-title":"Association of serum bilirubin with oxidant damage of human atherosclerotic plaques and the severity of atherosclerosis","volume":"18","author":"Lapenna","year":"2018","journal-title":"Clin. Exp. Med."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Tao, X., Wu, J., Wang, A., Xu, C., Wang, Z., and Zhao, X. (2019). Lower serum indirect bilirubin levels are inversely related to carotid intima-media thickness progression. Curr. Neurovasc. Res., 16.","DOI":"10.2174\/1567202616666190412153735"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S0021-9150(01)00601-3","article-title":"Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels","volume":"160","author":"Jirsa","year":"2002","journal-title":"Atherosclerosis"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.taap.2011.03.013","article-title":"Beneficial effects of carbon monoxide-releasing molecule-2 (CORM-2) on acute doxorubicin cardiotoxicity in mice: role of oxidative stress and apoptosis","volume":"253","author":"Soni","year":"2011","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ejphar.2017.10.031","article-title":"Carbon monoxide releasing molecule improves structural and functional cardiac recovery after myocardial injury","volume":"818","author":"Lakkisto","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.bbrc.2017.06.089","article-title":"CO-releasing molecules-2 attenuates ox-LDL-induced injury in HUVECs by ameliorating mitochondrial function and inhibiting Wnt\/\u03b2-catenin pathway","volume":"490","author":"Sun","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1177\/0748233714558084","article-title":"In vitro effects of exogenous carbon monoxide on oxidative stress and lipid metabolism in macrophages","volume":"32","author":"Petrick","year":"2016","journal-title":"Toxicol. Ind. Health"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"12638","DOI":"10.1016\/S0021-9258(18)37801-3","article-title":"The molecular cloning and characterization of murine ferritin heavy chain, a tumor necrosis factor-inducible gene","volume":"263","author":"Torti","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1681\/ASN.2008070788","article-title":"Ferritin prevents calcification and osteoblastic differentiation of vascular smooth muscle cells","volume":"20","author":"Zarjou","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1161\/ATVBAHA.118.312191","article-title":"Potential Role of H-Ferritin in Mitigating Valvular Mineralization","volume":"39","author":"Sikura","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1111\/jcmm.12682","article-title":"Pharmacological induction of ferritin prevents osteoblastic transformation of smooth muscle cells","volume":"20","author":"Becs","year":"2016","journal-title":"J. Cell. Mol. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.atherosclerosis.2014.04.028","article-title":"Ox-LDL induces endothelial cell apoptosis via the LOX-1-dependent endoplasmic reticulum stress pathway","volume":"235","author":"Hong","year":"2014","journal-title":"Atherosclerosis"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1161\/CIRCULATIONAHA.106.682054","article-title":"Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome","volume":"116","author":"Myoishi","year":"2007","journal-title":"Circulation"},{"key":"ref_95","first-page":"868","article-title":"Role of PERK\/eIF2\u03b1\/CHOP Endoplasmic Reticulum Stress Pathway in Oxidized Low-density Lipoprotein Mediated Induction of Endothelial Apoptosis","volume":"29","author":"Tao","year":"2016","journal-title":"Biomed. Environ. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"4032","DOI":"10.1074\/jbc.M113.524512","article-title":"Endoplasmic reticulum stress promotes macrophage-derived foam cell formation by up-regulating cluster of differentiation 36 (CD36) expression","volume":"289","author":"Yao","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1038\/nm.2067","article-title":"Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis","volume":"15","author":"Erbay","year":"2009","journal-title":"Nat. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1159\/000492522","article-title":"Endoplasmic Reticulum Stress Affects Lipid Metabolism in Atherosclerosis Via CHOP Activation and Over-Expression of miR-33","volume":"48","author":"Sun","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1089\/ars.2014.5851","article-title":"Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease","volume":"21","author":"Cao","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.freeradbiomed.2013.12.017","article-title":"Increased endoplasmic reticulum stress and Nrf2 repression in peripheral blood mononuclear cells of patients with stable coronary artery disease","volume":"68","author":"Mozzini","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Zhang, T., Hu, Q., Shi, L., Qin, L., Zhang, Q., and Mi, M. (2016). Equol Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice by Inhibiting Endoplasmic Reticulum Stress via Activation of Nrf2 in Endothelial Cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0167020"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Luo, Y., Sun, G., Dong, X., Wang, M., Qin, M., Yu, Y., and Sun, X. (2015). Isorhamnetin attenuates atherosclerosis by inhibiting macrophage apoptosis via PI3K\/AKT activation and HO-1 induction. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120259"},{"key":"ref_103","first-page":"117","article-title":"Isorhamnetin protects against bleomycin-induced pulmonary fibrosis by inhibiting endoplasmic reticulum stress and epithelial-mesenchymal transition","volume":"43","author":"Zheng","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1002\/ana.24159","article-title":"Toll-like receptor 2\/4 heterodimer mediates inflammatory injury in intracerebral hemorrhage","volume":"75","author":"Wang","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"5028","DOI":"10.3390\/ijms16035028","article-title":"Methemoglobin is an endogenous toll-like receptor 4 ligand-relevance to subarachnoid hemorrhage","volume":"16","author":"Kwon","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"20221","DOI":"10.1074\/jbc.M610737200","article-title":"Characterization of heme as activator of Toll-like receptor 4","volume":"282","author":"Figueiredo","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/1742-2094-9-46","article-title":"Heme activates TLR4-mediated inflammatory injury via MyD88\/TRIF signaling pathway in intracerebral hemorrhage","volume":"9","author":"Lin","year":"2012","journal-title":"J. Neuroinflammation"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13041-017-0305-z","article-title":"Heme molecule functions as an endogenous agonist of astrocyte TLR2 to contribute to secondary brain damage after intracerebral hemorrhage","volume":"10","author":"Min","year":"2017","journal-title":"Mol. Brain"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1161\/STROKEAHA.113.001038","article-title":"Toll-like receptor 4 antagonist attenuates intracerebral hemorrhage-induced brain injury","volume":"44","author":"Wang","year":"2013","journal-title":"Stroke"},{"key":"ref_110","first-page":"2432","article-title":"Silencing the gene encoding C\/EBP homologous protein lessens acute brain injury following ischemia\/reperfusion","volume":"7","author":"Wang","year":"2012","journal-title":"Neural Regen. Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1007\/s12035-016-9790-9","article-title":"Pharmacological Inhibition of PERK Attenuates Early Brain Injury After Subarachnoid Hemorrhage in Rats Through the Activation of Akt","volume":"54","author":"Yan","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3389\/fnins.2018.00111","article-title":"PERK Pathway Activation Promotes Intracerebral Hemorrhage Induced Secondary Brain Injury by Inducing Neuronal Apoptosis Both in Vivo and in Vitro","volume":"12","author":"Meng","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1172\/JCI78443","article-title":"Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1","volume":"125","author":"Schallner","year":"2015","journal-title":"J. Clin. Invest."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1093\/brain\/awm095","article-title":"Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage","volume":"130","author":"Wang","year":"2007","journal-title":"Brain"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1093\/jnen\/63.6.587","article-title":"Heme oxygenase in experimental intracerebral hemorrhage: the benefit of tin-mesoporphyrin","volume":"63","author":"Koeppen","year":"2004","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1177\/0271678X16655814","article-title":"Distinct role of heme oxygenase-1 in early- and late-stage intracerebral hemorrhage in 12-month-old mice","volume":"37","author":"Zhang","year":"2017","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/s00701-010-0750-2","article-title":"Time course of heme oxygenase-1 and oxidative stress after experimental intracerebral hemorrhage","volume":"153","author":"Wang","year":"2011","journal-title":"Acta Neurochir. (Wien)"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s12974-016-0490-1","article-title":"Deletion of the hemopexin or heme oxygenase-2 gene aggravates brain injury following stroma-free hemoglobin-induced intracerebral hemorrhage","volume":"13","author":"Ma","year":"2016","journal-title":"J. Neuroinflammation"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Chen-Roetling, J., Cai, Y., and Regan, R.F. (2014). Neuroprotective effect of heme oxygenase-2 knockout in the blood injection model of intracerebral hemorrhage. BMC Res. Notes, 7.","DOI":"10.1186\/1756-0500-7-561"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"3620","DOI":"10.1016\/S0021-9258(17)43139-5","article-title":"Iron-catalyzed hydroxyl radical formation. Stringent requirement for free iron coordination site","volume":"259","author":"Graf","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S1357-2725(99)00147-8","article-title":"Iron-induced lipid peroxidation and protein modification in endoplasmic reticulum membranes. Protection by stobadine","volume":"32","author":"Doval","year":"2000","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1023\/A:1024145212616","article-title":"Free radical-induced protein modification and inhibition of Ca2+-ATPase of cardiac sarcoplasmic reticulum","volume":"248","author":"Kaplan","year":"2003","journal-title":"Mol. Cell. Biochem."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1126\/science.1176639","article-title":"ER stress controls iron metabolism through induction of hepcidin","volume":"325","author":"Vecchi","year":"2009","journal-title":"Science"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.expneurol.2017.12.015","article-title":"CHOP induces apoptosis by affecting brain iron metabolism in rats with subarachnoid hemorrhage","volume":"302","author":"Zhao","year":"2018","journal-title":"Exp. Neurol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"e90777","DOI":"10.1172\/jci.insight.90777","article-title":"Inhibition of neuronal ferroptosis protects hemorrhagic brain","volume":"2","author":"Li","year":"2017","journal-title":"JCI insight"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"S90","DOI":"10.1161\/STROKEAHA.108.533125","article-title":"Deferoxamine Mesylate: A New Hope for Intracerebral Hemorrhage: From Bench to Clinical Trials","volume":"40","author":"Selim","year":"2009","journal-title":"Stroke"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"3110","DOI":"10.1177\/0271678X17709186","article-title":"Neuroprotection of brain-permeable iron chelator VK-28 against intracerebral hemorrhage in mice","volume":"37","author":"Li","year":"2017","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1186\/s12974-016-0709-1","article-title":"Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine","volume":"13","author":"LeBlanc","year":"2016","journal-title":"J. Neuroinflammation"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1126\/science.3029864","article-title":"Bilirubin is an antioxidant of possible physiological importance","volume":"235","author":"Stocker","year":"1987","journal-title":"Science"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"5918","DOI":"10.1073\/pnas.84.16.5918","article-title":"Antioxidant activity of albumin-bound bilirubin","volume":"84","author":"Stocker","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1016\/S0140-6736(58)91849-X","article-title":"Influence of light on the hyperbilirubin\u00c6mia of infants","volume":"271","author":"Cremer","year":"1958","journal-title":"Lancet"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"6865","DOI":"10.1021\/ja00388a103","article-title":"Phototherapy for neonatal jaundice. Configurational isomers of bilirubin","volume":"104","author":"McDonagh","year":"1982","journal-title":"J. Am. Chem. Soc."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1056\/NEJM195101112440201","article-title":"Erythroblastosis Fetalis","volume":"244","author":"Diamond","year":"1951","journal-title":"N. Engl. J. Med."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1542\/peds.89.5.809","article-title":"Evaluation and treatment of jaundice in the term newborn: a kinder, gentler approach","volume":"89","author":"Newman","year":"1992","journal-title":"Pediatrics"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1542\/peds.93.1.1","article-title":"Control of jaundice in preterm newborns by an inhibitor of bilirubin production: studies with tin-mesoporphyrin","volume":"93","author":"Valaes","year":"1994","journal-title":"Pediatrics"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/s005350070044","article-title":"Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance","volume":"35","author":"Kamisako","year":"2000","journal-title":"J. Gastroenterol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1007\/s00204-016-1835-3","article-title":"Bilirubin-induced ER stress contributes to the inflammatory response and apoptosis in neuronal cells","volume":"91","author":"Qaisiya","year":"2017","journal-title":"Arch. Toxicol."},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Schiavon, E., Smalley, J.L., Newton, S., Greig, N.H., and Forsythe, I.D. (2018). Neuroinflammation and ER-stress are key mechanisms of acute bilirubin toxicity and hearing loss in a mouse model. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0201022"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12974-018-1064-1","article-title":"Unconjugated bilirubin induces pyroptosis in cultured rat cortical astrocytes","volume":"15","author":"Feng","year":"2018","journal-title":"J. Neuroinflammation"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1097\/CCM.0b013e31822f0d64","article-title":"CORM-3, a carbon monoxide-releasing molecule, alters the inflammatory response and reduces brain damage in a rat model of hemorrhagic stroke*","volume":"40","author":"Yabluchanskiy","year":"2012","journal-title":"Crit. Care Med."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/jbt.10058","article-title":"Diabetes, oxidative stress, and antioxidants: a review","volume":"17","author":"Maritim","year":"2003","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1161\/CIRCRESAHA.110.223545","article-title":"Oxidative stress and diabetic complications","volume":"107","author":"Giacco","year":"2010","journal-title":"Circ. Res."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1681\/ASN.2005090997","article-title":"Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients","volume":"17","author":"Regidor","year":"2006","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.bbrc.2004.01.086","article-title":"Heme oxygenase-1 prevents superoxide anion-associated endothelial cell sloughing in diabetic rats","volume":"315","author":"Quan","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_145","first-page":"371","article-title":"Heme oxygenase-1 gene expression increases vascular relaxation and decreases inducible nitric oxide synthase in diabetic rats","volume":"51","author":"Ahmad","year":"2005","journal-title":"Cell. Mol. Biol. (Noisy-le-grand)"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.bbrc.2005.12.082","article-title":"Chronic CO levels have [corrected] a beneficial effect on vascular relaxation in diabetes","volume":"340","author":"Rodella","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1161\/HYPERTENSIONAHA.110.151423","article-title":"Adipocyte heme oxygenase-1 induction attenuates metabolic syndrome in both male and female obese mice","volume":"56","author":"Burgess","year":"2010","journal-title":"Hypertens. (Dallas, Tex. 1979)"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.2337\/db16-0020","article-title":"Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation","volume":"65","author":"Xie","year":"2016","journal-title":"Diabetes"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1177\/0960327116673169","article-title":"Hemin, a heme oxygenase-1 inducer, restores the attenuated cardioprotective effect of ischemic preconditioning in isolated diabetic rat heart","volume":"36","author":"Gupta","year":"2017","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1111\/fcp.12296","article-title":"Modulation of heme oxygenase-1 expression and activity affects streptozotocin-induced diabetic nephropathy in rats","volume":"31","author":"Ali","year":"2017","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1089\/ars.2017.7005","article-title":"Inhibition of miR-92a Suppresses Oxidative Stress and Improves Endothelial Function by Upregulating Heme Oxygenase-1 in db\/db Mice","volume":"28","author":"Gou","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.bbrc.2016.02.028","article-title":"MicroRNA-218 promotes high glucose-induced apoptosis in podocytes by targeting heme oxygenase-1","volume":"471","author":"Yang","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1681\/ASN.2004121082","article-title":"Heme oxygenase-2 deficiency contributes to diabetes-mediated increase in superoxide anion and renal dysfunction","volume":"17","author":"Goodman","year":"2006","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.freeradbiomed.2015.07.151","article-title":"Heme oxygenase-1-derived bilirubin protects endothelial cells against high glucose-induced damage","volume":"89","author":"He","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.2337\/db14-1391","article-title":"Unconjugated Bilirubin Mediates Heme Oxygenase-1\u2013Induced Vascular Benefits in Diabetic Mice","volume":"64","author":"Liu","year":"2015","journal-title":"Diabetes"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1177\/0003319716632394","article-title":"Total Bilirubin Levels Predict Subclinical Atherosclerosis in Patients With Prediabetes","volume":"67","author":"Hamur","year":"2016","journal-title":"Angiology"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1210\/en.2013-1667","article-title":"Bilirubin Increases Insulin Sensitivity in Leptin-Receptor Deficient and Diet-Induced Obese Mice Through Suppression of ER Stress and Chronic Inflammation","volume":"155","author":"Dong","year":"2014","journal-title":"Endocrinology"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/j.bbrc.2017.09.111","article-title":"Carbon monoxide regulates glycolysis-dependent NLRP3 inflammasome activation in macrophages","volume":"493","author":"Lee","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.vph.2014.02.001","article-title":"Induction of heme oxygenase-1 ameliorates vascular dysfunction in streptozotocin-induced type 2 diabetic rats","volume":"61","author":"Wang","year":"2014","journal-title":"Vascul. Pharmacol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1161\/ATVBAHA.116.306256","article-title":"Pathology of Human Coronary and Carotid Artery Atherosclerosis and Vascular Calcification in Diabetes Mellitus","volume":"37","author":"Yahagi","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1136\/hrt.78.5.472","article-title":"Cardiac valve calcification: characteristics of patients with calcification of the mitral annulus or aortic valve","volume":"78","author":"Boon","year":"1997","journal-title":"Heart"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.gene.2019.02.105","article-title":"Expression of LRP1 and CHOP genes associated with peripheral neuropathy in type 2 diabetes mellitus: Correlations with nerve conduction studies","volume":"702","author":"Watany","year":"2019","journal-title":"Gene"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1681\/ASN.2008090959","article-title":"Is the ER stressed out in diabetic kidney disease?","volume":"19","author":"Brosius","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1007\/s11064-015-1798-4","article-title":"Potential Role of Endoplasmic Reticulum Stress in Pathogenesis of Diabetic Retinopathy","volume":"41","author":"Salceda","year":"2016","journal-title":"Neurochem. Res."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/1475-2840-12-158","article-title":"Protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway plays a major role in reactive oxygen species (ROS)-mediated endoplasmic reticulum stress-induced apoptosis in diabetic cardiomyopathy","volume":"12","author":"Liu","year":"2013","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"111857","DOI":"10.1016\/j.jep.2019.111857","article-title":"Astragalus polysaccharides inhibits cardiomyocyte apoptosis during diabetic cardiomyopathy via the endoplasmic reticulum stress pathway","volume":"238","author":"Sun","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"244","DOI":"10.3109\/10715762.2014.997229","article-title":"Endoplasmic reticulum stress and Nrf2 repression in circulating cells of type 2 diabetic patients without the recommended glycemic goals","volume":"49","author":"Mozzini","year":"2015","journal-title":"Free Radic. Res."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.bcp.2016.12.009","article-title":"Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity","volume":"127","author":"Maamoun","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1038\/s41598-017-00936-9","article-title":"Tangluoning, a traditional Chinese medicine, attenuates in vivo and in vitro diabetic peripheral neuropathy through modulation of PERK\/Nrf2 pathway","volume":"7","author":"Yang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.jnutbio.2014.03.007","article-title":"Proanthocyanidins protect against early diabetic peripheral neuropathy by modulating endoplasmic reticulum stress","volume":"25","author":"Ding","year":"2014","journal-title":"J. Nutr. Biochem."},{"key":"ref_171","doi-asserted-by":"crossref","unstructured":"Kang, M.-K., Lee, E.-J., Kim, Y.-H., Kim, D.Y., Oh, H., Kim, S.-I., and Kang, Y.-H. (2018). Chrysin Ameliorates Malfunction of Retinoid Visual Cycle through Blocking Activation of AGE-RAGE-ER Stress in Glucose-Stimulated Retinal Pigment Epithelial Cells and Diabetic Eyes. Nutrients, 10.","DOI":"10.3390\/nu10081046"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s00204-012-0913-4","article-title":"Protection by chrysin, apigenin, and luteolin against oxidative stress is mediated by the Nrf2-dependent up-regulation of heme oxygenase 1 and glutamate cysteine ligase in rat primary hepatocytes","volume":"87","author":"Huang","year":"2013","journal-title":"Arch. Toxicol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.lfs.2019.03.037","article-title":"Arctigenin ameliorates renal impairment and inhibits endoplasmic reticulum stress in diabetic db\/db mice","volume":"223","author":"Zhang","year":"2019","journal-title":"Life Sci."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"497","DOI":"10.4062\/biomolther.2014.121","article-title":"Arctigenin Increases Hemeoxygenase-1 Gene Expression by Modulating PI3K\/AKT Signaling Pathway in Rat Primary Astrocytes","volume":"22","author":"Jeong","year":"2014","journal-title":"Biomol. Ther. (Seoul)"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1042\/CS20171432","article-title":"Endoplasmic reticulum stress\/autophagy pathway is involved in diabetes-induced neuronal apoptosis and cognitive decline in mice","volume":"132","author":"Kong","year":"2018","journal-title":"Clin. Sci. (Lond.)"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1007\/s12035-015-9666-4","article-title":"High-Glucose-Derived Oxidative Stress-Dependent Heme Oxygenase-1 Expression from Astrocytes Contributes to the Neuronal Apoptosis","volume":"54","author":"Yang","year":"2017","journal-title":"Mol. Neurobiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/15\/3675\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:10:14Z","timestamp":1760188214000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/15\/3675"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,26]]},"references-count":176,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2019,8]]}},"alternative-id":["ijms20153675"],"URL":"https:\/\/doi.org\/10.3390\/ijms20153675","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,26]]}}}