{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T23:48:29Z","timestamp":1772149709291,"version":"3.50.1"},"reference-count":80,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health, National, Heart, Lung, and Blood Institute","award":["R01 HL149727"],"award-info":[{"award-number":["R01 HL149727"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Coronavirus disease 2019 (COVID-19) causes cardiovascular complications, which contributes to the high mortality rate of the disease. Emerging evidence indicates that aberrant vascular smooth muscle cell (SMC) function is a key driver of vascular disease in COVID-19. While antivirals alleviate the symptoms of COVID-19, it is not known whether these drugs directly affect SMCs. Accordingly, the present study investigated the ability of three approved COVID-19 antiviral drugs to influence SMC function. Treatment of SMCs with remdesivir (RDV), but not molnupiravir or nirmatrelvir, inhibited cell proliferation, DNA synthesis, and migration without affecting cell viability. RDV also stimulated an increase in heme oxygenase-1 (HO-1) expression that was not observed with molnupiravir or nirmatrelvir. The induction of HO-1 by RDV was abolished by mutating the antioxidant responsive element of the promoter, overexpressing dominant-negative NF-E2-related factor-2 (Nrf2), or treating cells with an antioxidant. Finally, silencing HO-1 partly rescued the proliferative and migratory response of RDV-treated SMCs, and this was reversed by carbon monoxide and bilirubin. In conclusion, the induction of HO-1 via the oxidant-sensitive Nrf2 signaling pathway contributes to the antiproliferative and antimigratory actions of RDV by generating carbon monoxide and bilirubin. These pleiotropic actions of RDV may prevent occlusive vascular disease in COVID-19.<\/jats:p>","DOI":"10.3390\/antiox14080945","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T10:58:26Z","timestamp":1754564306000},"page":"945","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Selective Inhibition of Vascular Smooth Muscle Cell Function by COVID-19 Antiviral Drugs: Impact of Heme Oxygenase-1"],"prefix":"10.3390","volume":"14","author":[{"given":"Kelly J.","family":"Peyton","sequence":"first","affiliation":[{"name":"Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanna L.","family":"Durante","sequence":"additional","affiliation":[{"name":"Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6715-4352","authenticated-orcid":false,"given":"William","family":"Durante","sequence":"additional","affiliation":[{"name":"Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2025, March 21). WHO Coronavirus Disease (COVID-19) Dashboard. Available online: https:\/\/data.who.int\/dashboards\/covid19\/deaths?n=0."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41577-020-0311-8","article-title":"The trinity of COVID-19: Immunology, inflammation and intervention","volume":"20","author":"Tay","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1161\/CIRCRESAHA.120.317447","article-title":"The emerging threat of (micro) thrombosis in COVID-19 and its therapeutic implications","volume":"127","author":"McFadyen","year":"2020","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Nazerian, Y., Ghasemi, M., Yassaghi, Y., Nazerian, A., and Hashemi, S.M. (2022). Role of SARS-CoV-2-induced cytokine storm in multi-organ failure: Molecular pathways and potential therapeutic options. Int. Immunopharmacol., 113.","DOI":"10.1016\/j.intimp.2022.109428"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1038\/s41591-022-01837-9","article-title":"A multisystem, cardio-renal investigation of post-COVID-19 illness","volume":"28","author":"Morrow","year":"2022","journal-title":"Nat. Med."},{"key":"ref_6","first-page":"1775","article-title":"Case-fatality rate and characteristics of patients dying in relation to COVID-19","volume":"323","author":"Onder","year":"2020","journal-title":"JAMA"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Guo, Y.-R., Cao, D.-Q., Hong, Z.-S., Tan, Y.-Y., Chen, S.-D., Jin, H.-J., Tan, K.S., Wang, D.-Y., and Yan, Y. (2020). The origin, transmission, and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak\u2014An update on the status. Mil. Med. Res., 7.","DOI":"10.1186\/s40779-020-00240-0"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3038","DOI":"10.1093\/eurheartj\/ehaa623","article-title":"COVID-19 is, in the end, an endothelial disease","volume":"41","author":"Libby","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.yjmcc.2021.11.010","article-title":"Endothelial contribution to COVID-19: An update on mechanisms and therapeutic implications","volume":"164","author":"Ma","year":"2022","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1016\/j.mayocp.2021.06.027","article-title":"Viral endothelial dysfunction: A unifying mechanism for COVID-19","volume":"96","author":"Prasad","year":"2021","journal-title":"Mayo Clin. Proc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1161\/CIRCULATIONAHA.120.052824","article-title":"Lack of evidence of angiotensin-converting enzyme 2 expression and replicative infection by SARS-CoV-2 in human endothelial cells","volume":"143","author":"McCraken","year":"2021","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.stemcr.2021.02.008","article-title":"SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function","volume":"16","author":"Marchiano","year":"2021","journal-title":"Stem. Cell Rep."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Suzuki, Y.J., Nikolaienko, S.I., Dibrova, V.A., Dibrova, Y.V., Vasylyk, V.M., Novikov, M.Y., Shults, N.V., and Gychka, S.G. (2021). SARS-CoV-2 spike protein-mediated cell signaling in lung vascular cells. Vasc. Pharmacol., 137.","DOI":"10.1016\/j.vph.2020.106823"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Martinez-Salazar, B., Holwerda, M., Studle, C., Piragyte, I., Mercader, N., Engelhardt, B., Rieben, R., and Doring, Y. (2022). COVID-19 and the vasculature: Current aspects and long-term consequences. Front. Cell Devel. Biol., 10.","DOI":"10.3389\/fcell.2022.824851"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1159\/000519542","article-title":"Increase in chondroitin sulfate and decline in arylsulfatase B may contribute to pathophysiology of COVID-19 respiratory failure","volume":"89","author":"Tzankov","year":"2022","journal-title":"Pathobiology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1161\/CIRCRESAHA.121.320460","article-title":"Vascular dysfunction of COVID-19 is partially reversed long-term","volume":"130","author":"Zanoli","year":"2022","journal-title":"Circ. Res."},{"key":"ref_17","first-page":"371","article-title":"Vascular mechanisms of post-COVID-19 conditions: Rho-kinase is a novel target for therapy","volume":"9","author":"Sykes","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Islam, T., Hasan, M., Rhamna, M.S., and Islam, M.R. (2022). Comparative evaluation of authorized drugs for treating COVID-19 patients. Health Sci. Rep., 5.","DOI":"10.1002\/hsr2.671"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1126\/science.abc1560","article-title":"Structural basis for the inhibition of RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir","volume":"368","author":"Yin","year":"2020","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gordon, C.J., Tchesnokov, E.P., Schinazi, R.F., and Gotte, M. (2021). Molnupiravir promotes SARS-CoV-2 mutagenesis vi the RNA template. J. Biol. Chem., 297.","DOI":"10.1016\/j.jbc.2021.100770"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1126\/science.abl4784","article-title":"An oral SARS-CoV-2 M(pro) inhibitor candidate for the treatment of COVID-19","volume":"374","author":"Owen","year":"2021","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1152\/physrev.00003.2016","article-title":"Heme oxygenases in cardiovascular health and disease","volume":"96","author":"Ayer","year":"2016","journal-title":"Physiol. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1111\/j.1582-4934.2006.tb00427.x","article-title":"Role of carbon monoxide in cardiovascular function","volume":"10","author":"Durante","year":"2006","journal-title":"J. Cell. Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Durante, W. (2020). Targeting heme oxygenase-1 in the arterial response to injury and disease. Antioxidants, 9.","DOI":"10.3390\/antiox9090829"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.2741\/3860","article-title":"Protective role of heme oxygenase-1 against inflammation in atherosclerosis","volume":"16","author":"Durante","year":"2011","journal-title":"Front. Biosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.ajpath.2016.11.011","article-title":"Modulation of antiviral immunity by heme oxygenase-1","volume":"187","author":"Espinosa","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wagener, F.A.D.T.G., Pickkers, P., Peterson, S.J., Immenschuh, S., and Abraham, N.G. (2020). Targeting the heme-heme oxygenase system to prevent severe complications following COVID-19 infections. Antioxidants, 96.","DOI":"10.3390\/antiox9060540"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.freeradbiomed.2020.10.016","article-title":"Heme oxygenase-1 modulation: A potential therapeutic target for COVID-19 and associated complications","volume":"161","author":"Singh","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Rossi, M., Piagnerelli, M., Van Meerhaeghe, A., and Boudjeltia, K.Z. (2020). Heme oxygenase-1 (HO-1) cytoprotective pathway: A potential treatment strategy against coronavirus disease 2019 (COVID-19)-induced cytokine storm. Med. Hypotheses, 144.","DOI":"10.1016\/j.mehy.2020.110242"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.freeradbiomed.2016.03.003","article-title":"Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial dysfunction","volume":"94","author":"Liu","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_31","first-page":"1051","article-title":"Nelfinavir induces adipocyte insulin resistance through induction of oxidative stress: Differential protective effect of antioxidant agents","volume":"11","author":"Rudich","year":"2002","journal-title":"Antiviral Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1038\/sj.bjp.0706023","article-title":"The HIV protease inhibitor ritonavir synergizes with butyrate for the induction of apoptotic cell death and mediates expression of heme oxygenase-1 in DLD-1 colon carcinoma cells","volume":"143","author":"Muhl","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1097\/QAD.0000000000002516","article-title":"HIV protease inhibitor ritonavir induces renal fibrosis and dysfunction: Role of platelet-derived TGF-\u03b21 and intervention via antioxidant pathway","volume":"34","author":"Laurence","year":"2020","journal-title":"AIDS"},{"key":"ref_34","first-page":"H617","article-title":"Plasmin potentiates induction of nitric oxide synthesis by interleukin-1 beta in vascular smooth muscle cells","volume":"264","author":"Durante","year":"1993","journal-title":"Am. J. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4443","DOI":"10.1182\/blood.V99.12.4443","article-title":"Heme oxygenase-derived carbon monoxide is an autocrine inhibitor of vascular smooth muscle cell growth","volume":"99","author":"Peyton","year":"2002","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1124\/jpet.111.181784","article-title":"Compound C inhibits vascular smooth muscle cell proliferation and migration in an AMPK-activated protein kinase-independent fashion","volume":"338","author":"Peyton","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Peyton, K.J., Shebib, A.R., Azam, A.M., Liu, X.M., Tulis, D.A., and Durante, W. (2012). Bilirubin inhibits neointima formation and vascular smooth muscle cell proliferation and migration. Front. Pharmacol., 3.","DOI":"10.3389\/fphar.2012.00048"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"H1634","DOI":"10.1152\/ajpheart.00872.2012","article-title":"Physiologic cyclic strain promotes endothelial cell survival via the induction of heme oxygenase-1","volume":"304","author":"Liu","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1074\/jbc.M410413200","article-title":"Endoplasmic reticulum stress stimulates heme oxygenase-1 gene expression in vascular smooth muscle cells. Role in cell survival","volume":"280","author":"Liu","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.cardiores.2007.03.004","article-title":"Nitric oxide stimulates heme oxygenase-1 gene transcription via the Nrf2\/ARE complex to promote vascular smooth muscle cell survival","volume":"75","author":"Liu","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1161\/01.ATV.19.11.2666","article-title":"Platelet-derived growth factor stimulates heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle cells","volume":"19","author":"Durante","year":"1999","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/S0140-6736(20)31022-9","article-title":"Remdesivir in adults with severe COVID-19: A randomized, double-blind, placebo-controlled multicenter trial","volume":"395","author":"Wang","year":"2020","journal-title":"Lancet"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Painter, W.P., Holman, W., Bush, J.A., Almazedi, F., Malik, H., Eraut, N.C.J.E., Morin, M.J., Szewczyk, L.J., and Painter, G.R. (2021). Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2. Antimicrob. Agents Chemother., 65.","DOI":"10.1128\/AAC.02428-20"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1111\/cts.13292","article-title":"PF-07321332 (Nirmatrelvir) does not interact with human ENT1 or ENT2: Implications for COVID-19 patients","volume":"15","author":"Hau","year":"2022","journal-title":"Clin. Transl. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/89068","article-title":"Heme oxygenase-1 protects against vascular constriction and proliferation","volume":"7","author":"Duckers","year":"2001","journal-title":"Nat. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0021-9150(00)00552-9","article-title":"Heme oxygenase-1 attenuates vascular remodeling following balloon injury in rat carotid arteries","volume":"155","author":"Tulis","year":"2001","journal-title":"Atherosclerosis"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1161\/ATVBAHA.109.197822","article-title":"HO-1 and CO decrease platelet-derived growth factor-induced vascular smooth muscle cell migration via inhibition of Nox1","volume":"30","author":"Rodriguez","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1161\/ATVBAHA.108.165811","article-title":"KLF2 primes the antioxidant transcription factor Nrf2 for activation in endothelial cells","volume":"28","author":"Fledderus","year":"2008","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1161\/CIRCRESAHA.108.191114","article-title":"Induction of prostacyclin by steady laminar shear stress suppresses tumor necrosis factor-\u03b1 biosynthesis via heme oxygenase-1 in human endothelial cells","volume":"104","author":"Totani","year":"2009","journal-title":"Circ. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1161\/01.ATV.17.12.3481","article-title":"HDL-induced prostacyclin release in smooth muscle cells is dependent on cyclooxygenase-2 (Cox-2)","volume":"17","author":"Vinals","year":"1997","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0090-6980(94)90074-4","article-title":"NS-398, a new anti-inflammatory agent, selectively inhibits prostacyclin G\/H synthase\/cyclooxygenase (COX-2) activity in vitro","volume":"47","author":"Futaki","year":"1994","journal-title":"Prostaglandins"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1007\/s00204-022-03306-1","article-title":"The potential of remdesivir to affect function, metabolism and proliferation of cardiac and kidney cells in vitro","volume":"96","author":"Merches","year":"2022","journal-title":"Arch. Toxicol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Zhang, J., Zhang, X., Guo, X., Li, W., Zhang, T., Chai, D., Liu, Y., Chen, L., Ai, X., and Zhou, T. (2024). Remdesivir alleviates skin fibrosis by suppressing TGF-\u03b21 signaling pathway. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0305927"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Bjork, J.A., and Wallace, K.B. (2021). Remdesivir; molecular and functional measures of mitochondrial safety. Toxic. Appl. Pharmacol., 433.","DOI":"10.1016\/j.taap.2021.115783"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Xu, Y., Barauskas, O., Kim, C., Babusis, D., Murakami, E., Kornyeyev, D., Lee, G., Stepan, G., Perron, M., and Bannister, R. (2021). Off-target in vitro profiling demonstrates that remdesivir is a highly selective antiviral agent. Antimicrob. Agents Chemother., 65.","DOI":"10.1128\/AAC.02237-20"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/09603271221089257","article-title":"An in vitro study on anti-carcinogenic effect of remdesivir in human ovarian cancer cells via generation of reactive oxygen species","volume":"41","author":"Lee","year":"2022","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1074\/jbc.M109.009886","article-title":"Induction of the cytoprotective enzyme heme oxygenase-1 by statins is enhanced in vascular endothelium exposed to laminar shear stress and impaired by disturbed blood flow","volume":"284","author":"Ali","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_58","first-page":"148","article-title":"Effects of remdesivir on liver enzymes, oxidative stress and liver histopathology in rats","volume":"9","author":"Abbasi","year":"2024","journal-title":"Int. J. Ecotoxicol. Ecobiol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Nugnes, R., Orlo, E., Russo, C., Lavorgna, M., and Isidori, M. (2024). Comprehensive eco-geno-toxicity and environmental risk of common antiviral drugs in aquatic environments post pandemic. J. Hazard Mater., 480.","DOI":"10.1016\/j.jhazmat.2024.135947"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Kong, K., Chang, Y., Qiao, H., Zhao, C., Chen, X., Rong, K., Zhang, P., Jin, M., Zhang, J., and Li, H. (2022). Paxlovid accelerates cartilage degeneration and senescence through activating endoplasmic reticulum stress and interfering redox homeostasis. J. Transl. Med., 20.","DOI":"10.1186\/s12967-022-03770-4"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Martinez, A. (2021). Electron donor-acceptor capacity of selected pharmaceuticals against COVID-19. Antioxidants, 10.","DOI":"10.3390\/antiox10060979"},{"key":"ref_62","first-page":"1","article-title":"Molnupiravir, favipiravir and other antiviral drugs with proposed potentials for management of COVID-19: A concern on antioxidant aspect","volume":"13","author":"Yasri","year":"2022","journal-title":"Int. J. Biochem. Mol. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Bartolini, D., Stabile, A.M., Bastianelli, S., Giustarini, D., Pierucci, S., Busti, C., Vacca, C., Gidari, A., Francisci, D., and Castronari, R. (2021). SARS-CoV2 infection impairs the metabolism and redox function of cellular glutathione. Red. Biol., 45.","DOI":"10.1016\/j.redox.2021.102041"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1093\/cvr\/cvab311","article-title":"Remdesivir induces persistent mitochondrial and structural damage in human induced pluripotent stem cell-derived cardiomyocytes","volume":"118","author":"Kwok","year":"2021","journal-title":"Cardiovasc. Res."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"DeFoor, N., Paul, S., Li, S., Basso, E.K.G., Stevenson, V., Browning, J.L., Prater, A.K., Brindley, S., Tao, G., and Pickrell, A.A. (2023). Remdesivir increases mtDNA copy number causing mild alterations to oxidative phosphorylation. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-42704-y"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.toxlet.2021.07.015","article-title":"Little in vitro effect of remdesivir on mitochondrial respiration and monoamine oxidase activity in isolated mitochondria","volume":"350","author":"Fisar","year":"2021","journal-title":"Tox. Lett."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1128\/MCB.23.22.8137-8151.2003","article-title":"Distinct cysteine residues in keap1 are required for keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventative agents and oxidative stress","volume":"23","author":"Zhang","year":"2003","journal-title":"Mol. Cell Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/nm817","article-title":"Carbon monoxide suppresses artherosclerotic lesions associated with chronic graft rejection and with balloon injury","volume":"9","author":"Otterbein","year":"2003","journal-title":"Nat. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1161\/CIRCULATIONAHA.104.528802","article-title":"Bilirubin: A natural inhibitor of vascular smooth muscle proliferation","volume":"112","author":"Ollinger","year":"2005","journal-title":"Circulation"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1161\/01.ATV.0000258868.80079.4d","article-title":"Nrf2 gene transfer induces antioxidant enzymes and suppresses smooth muscle cell growth in vitro and reduces oxidative stress in rabbit aorta in vivo","volume":"27","author":"Levonen","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1161\/ATVBAHA.112.300614","article-title":"Redox-sensitive transcription factor Nrf2 regulates vascular smooth muscle cell migration and neointimal hyperplasia","volume":"33","author":"Ashino","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.cbi.2019.03.002","article-title":"Inhibition of mitochondrial complex I activity attenuates neointimal hyperplasia by inhibiting smooth muscle cell proliferation and migration","volume":"304","author":"Yin","year":"2019","journal-title":"Chem. Biol. Interact."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s12192-022-01296-8","article-title":"Transcription factor Nrf2 as a potential therapeutic agent for COVID-19","volume":"28","author":"Wang","year":"2023","journal-title":"Cell Stress Chap."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Olagnier, D., Farahani, E., Thyrsted, J., Blay-Cadanet, J., Herengt, A., Idorn, M., Hait, A., Hernaez, B., Knudson, A., and Iversen, M.B. (2020). SARS-CoV2-mediated suppression of Nrf2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumurate. Nat. Commun., 11.","DOI":"10.1038\/s41467-020-19363-y"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Qu, Y., Haas de Mello, A., Morris, D.R., Jones-Hall, Y.L., Ivanciuc, T., Sattler, R.A., Paessler, S., Menachery, V.D., Garafolo, R.P., and Casola, A. (2023). SARS-CoV-2 inhibits Nrf2-mediated antioxidant responses in airway epithelial cells and in the lung of a murine model of infection. Microbiol. Spectr., 11.","DOI":"10.1128\/spectrum.00378-23"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.trsl.2015.06.011","article-title":"Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation","volume":"167","author":"Ryter","year":"2016","journal-title":"Transl. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1126\/science.add2962","article-title":"Endothelial inflammation in COVID-19: Disrupted endothelial function underlies the multiorgan complications of COVID-19","volume":"386","author":"Libby","year":"2024","journal-title":"Science"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1161\/CIRCRESAHA.107.158998","article-title":"Heme oxygenase-1 deficiency accelerates formation of arterial thrombosis through oxidative damage to endothelium, which is rescued by inhaled carbon monoxide","volume":"101","author":"True","year":"2007","journal-title":"Circ. Res."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Chung, J., Pierce, J., Franklin, C., Olson, R.M., Morrison, A.R., and Amos-Landgraf, J. (2025). Translating animal models of SARS-CoV-2 infection to vascular, neurological and gastrointestinal manifestations of COVID-19. Dis. Models Mech., 18.","DOI":"10.1242\/dmm.052086"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"10919","DOI":"10.1073\/pnas.94.20.10919","article-title":"Heme oxygenase 1 is required for mammalian iron utilization","volume":"94","author":"Poss","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/8\/945\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:19:51Z","timestamp":1760033991000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/8\/945"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,31]]},"references-count":80,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["antiox14080945"],"URL":"https:\/\/doi.org\/10.3390\/antiox14080945","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,31]]}}}