{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T16:17:22Z","timestamp":1768666642437,"version":"3.49.0"},"reference-count":75,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:00:00Z","timestamp":1768435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hull and East Riding Cardiac Trust Fund"},{"name":"Tertiary Education Trust Fund"},{"name":"University of Benin, Nigeria"},{"name":"Hull York Medical School, University of Hull, UK"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Activation of JAK\/STAT and MAPK\/ERK1,2 signalling pathways has been shown to increase the production of reactive oxygen species (ROS) in multiple cell types involved in cardiovascular diseases (CVDs), including vascular smooth muscle cells (VSMCs). However, these have not yet been studied in human saphenous vein SMCs (HSVSMCs) responsible for the maladaptive remodelling leading to saphenous vein graft failure (VGF), to which patients with type 2 diabetes mellitus (T2DM) are more susceptible. Therefore, this study aimed to evaluate the contributions of the JAK\/STAT and MAPK\/ERK1,2 pathways towards production of mitochondrial ROS (mROS) in HSVSMCs from T2DM patients versus non-diabetic controls. HSVSMCs explanted from surplus HSV tissues from consenting patients undergoing coronary artery bypass graft surgery were stimulated in vitro with mitogenic stimuli known to be involved in neointimal hyperplasia (NIH) and VGF, which are known activators of the JAK\/STAT and the MAPK\/ERK1,2 signalling pathways. Flow cytometry was then used to analyse the production of mROS (superoxide) in MitoSOX-stained HSVSMCs. Additionally, we examined the effect of ruxolitinib and trametinib, selective inhibitors of JAK1\/2 and MEK1\/2 signalling pathways, respectively, on mROS levels in these cells. From our findings, mROS production was significantly higher in HSVSMCs from T2DM patients versus non-diabetic controls. Activation of either the JAK\/STAT or MAPK\/ERK1,2 signalling pathways did not significantly alter the production of mROS in HSVSMCs from both T2DM and non-diabetic patients. However, inhibition of JAK\/STAT and MAPK\/ERK1,2 signalling pathways with ruxolitinib and trametinib, respectively, resulted in a significant reduction in mROS in HSVSMCs from both T2DM and non-diabetic patients. Our findings demonstrate a JAK\/STAT- and MAPK\/ERK1,2-mediated production of mROS in HSVSMCs. Hence, they are potential targets for drug development to limit ROS production in ROS-driven proliferation and migration of HSVSMCs responsible for VGF.<\/jats:p>","DOI":"10.3390\/cells15020159","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T11:13:21Z","timestamp":1768475601000},"page":"159","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of the JAK and MEK Pathways Limits Mitochondrial ROS Production in Human Saphenous Vein Smooth Muscle Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4638-6522","authenticated-orcid":false,"given":"Israel O.","family":"Bolanle","sequence":"first","affiliation":[{"name":"Biomedical Institute for Multimorbidity, Centre for Biomedicine, Hull York Medical School, University of Hull, Hull HU6 7RX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James P.","family":"Hobkirk","sequence":"additional","affiliation":[{"name":"School of Cardiovascular & Metabolic Health, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1826-6686","authenticated-orcid":false,"given":"Mahmoud","family":"Loubani","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4423-5058","authenticated-orcid":false,"given":"Roger G.","family":"Sturmey","sequence":"additional","affiliation":[{"name":"Biomedical Institute for Multimorbidity, Centre for Biomedicine, Hull York Medical School, University of Hull, Hull HU6 7RX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9803-7164","authenticated-orcid":false,"given":"Timothy M.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Biomedical Institute for Multimorbidity, Centre for Biomedicine, Hull York Medical School, University of Hull, Hull HU6 7RX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12944-021-01435-7","article-title":"The impact of reactive oxygen species in the development of cardiometabolic disorders: A review","volume":"20","author":"Akhigbe","year":"2021","journal-title":"Lipids Health Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1006\/jmcc.1998.0862","article-title":"Age-related decrease in cardiac tolerance to oxidative stress","volume":"31","author":"Abete","year":"1999","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1016\/j.numecd.2021.01.017","article-title":"Revascularisation of type 2 diabetics with coronary artery disease: Insights and therapeutic targeting of O-GlcNAcylation","volume":"31","author":"Bolanle","year":"2021","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1139\/cjpp-2017-0225","article-title":"Glycosylation with O-linked \u03b2-N-acetylglucosamine induces vascular dysfunction via production of superoxide anion\/reactive oxygen species","volume":"96","author":"Neves","year":"2018","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4350965","DOI":"10.1155\/2016\/4350965","article-title":"ROS and ROS-mediated cellular signaling","volume":"2016","author":"Zhang","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"792639","DOI":"10.1155\/2011\/792639","article-title":"Mitogen-activated protein kinases and reactive oxygen species: How can ROS activate MAPK pathways?","volume":"2011","author":"Son","year":"2011","journal-title":"J. Signal Transduct."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/j.freeradbiomed.2008.06.009","article-title":"Ethyl pyruvate has an anti-inflammatory effect by inhibiting ROS-dependent STAT signaling in activated microglia","volume":"45","author":"Kim","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1074\/jbc.M307251200","article-title":"Reactive oxygen species mediate virus-induced STAT activation: Role of tyrosine phosphatases","volume":"279","author":"Liu","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"C1640","DOI":"10.1152\/ajpcell.1998.275.6.C1640","article-title":"Activation of the JAK-STAT pathway by reactive oxygen species","volume":"275","author":"Simon","year":"1998","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1002\/biof.5520170128","article-title":"Redox signaling and the MAP kinase pathways","volume":"17","author":"Torres","year":"2003","journal-title":"Biofactors"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1089\/ars.2006.8.1775","article-title":"Reactive oxygen species-induced activation of the MAP kinase signaling pathways","volume":"8","author":"McCubrey","year":"2006","journal-title":"Antioxid. Redox Signal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"L1005","DOI":"10.1152\/ajplung.2000.279.6.L1005","article-title":"Reactive oxygen species in cell signaling","volume":"279","author":"Thannickal","year":"2000","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hong, Y., Boiti, A., Vallone, D., and Foulkes, N.S. (2024). Reactive oxygen species signaling and oxidative stress: Transcriptional regulation and evolution. Antioxidants, 13.","DOI":"10.3390\/antiox13030312"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7269","DOI":"10.1073\/pnas.81.23.7269","article-title":"Detection of superoxide generated by endothelial cells","volume":"81","author":"Rosen","year":"1984","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"C1543","DOI":"10.1152\/ajpcell.1997.272.5.C1543","article-title":"Induction of human endothelial cell apoptosis requires both heat shock and oxidative stress responses","volume":"272","author":"Wang","year":"1997","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Burtenshaw, D., Hakimjavadi, R., Redmond, E.M., and Cahill, P.A. (2017). Nox, reactive oxygen species and regulation of vascular cell fate. Antioxidants, 6.","DOI":"10.3390\/antiox6040090"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.redox.2015.10.009","article-title":"Thrombin-induced reactive oxygen species generation in platelets: A novel role for protease-activated receptor 4 and GPIb\u03b1","volume":"6","author":"Carrim","year":"2015","journal-title":"Redox Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.tibs.2010.04.002","article-title":"Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes","volume":"35","author":"Hamanaka","year":"2010","journal-title":"Trends Biochem. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1039\/C4MB00571F","article-title":"Cysteine-mediated redox signalling in the mitochondria","volume":"11","author":"Bak","year":"2015","journal-title":"Mol. Biosyst."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"162","DOI":"10.3390\/diabetology5020013","article-title":"Do T2DM and Hyperglycaemia Affect the Expression Levels of the Regulating Enzymes of Cellular O-GlcNAcylation in Human Saphenous Vein Smooth Muscle Cells?","volume":"5","author":"Bolanle","year":"2024","journal-title":"Diabetology"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Bolanle, O.I., Moshapa, F.T., Durham, G.A., Hobkirk, J.P., Riches-Suman, K., Loubani, M., Sturmey, R.G., and Palmer, T. (2025). JAK and MEK Pathways as Therapeutic Targets for Saphenous Vein Smooth Muscle Cell Dysfunction in Type 2 Diabetes via Regulation of Mitochondrial Activity. bioRxiv.","DOI":"10.1101\/2025.10.17.682556"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100466","DOI":"10.1016\/j.xpro.2021.100466","article-title":"A flow-cytometry-based protocol for detection of mitochondrial ROS production under hypoxia","volume":"2","author":"Yang","year":"2021","journal-title":"STAR Protoc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"290","DOI":"10.2174\/1573403X14666180702152436","article-title":"Reactive oxygen species as intracellular signaling molecules in the cardiovascular system","volume":"14","author":"Krylatov","year":"2018","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1161\/CIRCRESAHA.114.300559","article-title":"Cardiac mitochondria and reactive oxygen species generation","volume":"114","author":"Chen","year":"2014","journal-title":"Circ. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.bbadis.2009.10.014","article-title":"Enhanced ROS production by NADPH oxidase is correlated to changes in antioxidant enzyme activity in human heart failure","volume":"1802","author":"Borchi","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.yjmcc.2009.04.004","article-title":"NADPH oxidase signaling and cardiac myocyte function","volume":"47","author":"Akki","year":"2009","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1042\/BST0340960","article-title":"Redox signalling involving NADPH oxidase-derived reactive oxygen species","volume":"34","author":"Dworakowski","year":"2006","journal-title":"Biochem. Soc. Trans."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.cardiores.2006.03.016","article-title":"NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure","volume":"71","author":"Murdoch","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.yjmcc.2007.01.009","article-title":"NADPH oxidase-dependent redox signaling in human heart failure: Relationship between the left and right ventricle","volume":"42","author":"Nediani","year":"2007","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1042\/CS20070430","article-title":"MAPK signalling in cardiovascular health and disease: Molecular mechanisms and therapeutic targets","volume":"115","author":"Muslin","year":"2008","journal-title":"Clin. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"16884","DOI":"10.1074\/jbc.RA119.009592","article-title":"Reactive oxygen species (ROS) generation is stimulated by \u03ba opioid receptor activation through phosphorylated c-Jun N-terminal kinase and inhibited by p38 mitogen-activated protein kinase (MAPK) activation","volume":"294","author":"Schattauer","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/s42003-020-0988-z","article-title":"High-content fluorescence imaging with the metabolic flux assay reveals insights into mitochondrial properties and functions","volume":"3","author":"Little","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_33","first-page":"361","article-title":"MitoSOX-based flow cytometry for detecting mitochondrial ROS","volume":"2","author":"Kauffman","year":"2016","journal-title":"React. Oxyg. Species (Apex)"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101574","DOI":"10.1016\/j.redox.2020.101574","article-title":"Interleukin-6 trans-signaling inhibition prevents oxidative stress in a mouse model of early diabetic retinopathy","volume":"34","author":"Robinson","year":"2020","journal-title":"Redox Biol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Didion, S.P. (2017). Cellular and oxidative mechanisms associated with interleukin-6 signaling in the vasculature. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122563"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.4049\/jimmunol.161.5.2567","article-title":"The up-regulation of IL-6 and IL-8 in human endothelial cells by activated protein C","volume":"161","author":"Hooper","year":"1998","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1111\/j.1365-2249.1994.tb06148.x","article-title":"Histamine induces IL-6 production by human endothelial cells","volume":"98","author":"Delneste","year":"1994","journal-title":"Clin. Exp. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1007\/BF01987902","article-title":"Hypoxia\/reoxygenation stimulates endothelial cells to promote interleukin-1 and interleukin-6 production. Effects of free radical scavengers","volume":"37","author":"Ala","year":"1992","journal-title":"Agents Actions"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"L1057","DOI":"10.1152\/ajplung.1999.277.5.L1057","article-title":"Endothelial permeability and IL-6 production during hypoxia: Role of ROS in signal transduction","volume":"277","author":"Ali","year":"1999","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11463","DOI":"10.1074\/jbc.270.19.11463","article-title":"Induction of interleukin 6 (IL-6) by hypoxia in vascular cells: Central role of the binding site for nuclear factor-IL-6","volume":"270","author":"Yan","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1042\/CS20040174","article-title":"Role of cytokines in cardiovascular diseases: A focus on endothelial responses to inflammation","volume":"108","author":"Kofler","year":"2005","journal-title":"Clin. Sci."},{"key":"ref_42","first-page":"21","article-title":"NADPH oxidase-derived reactive oxygen species in the regulation of endothelial phenotype","volume":"60","author":"Dworakowski","year":"2008","journal-title":"Pharmacol. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1007\/s00395-008-0733-0","article-title":"The role of inflammatory cytokines in endothelial dysfunction","volume":"103","author":"Zhang","year":"2008","journal-title":"Basic Res. Cardiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.bcp.2009.04.029","article-title":"Inflammatory cytokines in vascular dysfunction and vascular disease","volume":"78","author":"Sprague","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1096\/fj.01-1036fje","article-title":"Platelet-derived growth factor activates production of reactive oxygen species by NAD (P) H-oxidase in smooth muscle cells through Gi1, 2","volume":"17","author":"Kreuzer","year":"2003","journal-title":"FASEB J."},{"key":"ref_46","first-page":"374","article-title":"Control of PDGF-induced reactive oxygen species (ROS) generation and signal transduction in human lens epithelial cells","volume":"13","author":"Chen","year":"2007","journal-title":"Mol. Vis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1046\/j.1523-1755.1998.00212.x","article-title":"Angiotensin II-mediated expression of p27Kip1 and induction of cellular hypertrophy in renal tubular cells depend on the generation of oxygen radicals","volume":"54","author":"Hannken","year":"1998","journal-title":"Kidney Int."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"H1626","DOI":"10.1152\/ajpheart.1996.271.4.H1626","article-title":"Expression of phagocyte NADPH oxidase components in human endothelial cells","volume":"271","author":"Jones","year":"1996","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1172\/JCI115641","article-title":"Human fat cells possess a plasma membrane-bound H2O2-generating system that is activated by insulin via a mechanism bypassing the receptor kinase","volume":"89","author":"Kather","year":"1992","journal-title":"J. Clin. Investig."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.redox.2017.11.012","article-title":"Chicoric acid prevents PDGF-BB-induced VSMC dedifferentiation, proliferation and migration by suppressing ROS\/NF\u03baB\/mTOR\/P70S6K signaling cascade","volume":"14","author":"Lu","year":"2018","journal-title":"Redox Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3018584","DOI":"10.1155\/2019\/3018584","article-title":"Increased circulating levels of interleukin-6 affect the redox balance in skeletal muscle","volume":"2019","author":"Forcina","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Charras, A., Arvaniti, P., Le Dantec, C., Dalekos, G.N., Zachou, K., Bordron, A., and Renaudineau, Y. (2019). JAK inhibitors and oxidative stress control. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02814"},{"key":"ref_53","first-page":"36","article-title":"PRACTICE POINTER: Primary Sj\u00f6gren syndrome","volume":"345","author":"Bosch","year":"2012","journal-title":"BMJ"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1124\/pr.59.3.3","article-title":"The intrarenal renin-angiotensin system: From physiology to the pathobiology of hypertension and kidney disease","volume":"59","author":"Kobori","year":"2007","journal-title":"Pharmacol. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1172\/JCI115881","article-title":"Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II","volume":"90","author":"Gibbons","year":"1992","journal-title":"J. Clin. Investig."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S1357-2725(02)00271-6","article-title":"Inflammation and angiotensin II","volume":"35","author":"Suzuki","year":"2003","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1161\/01.CIR.103.3.448","article-title":"Angiotensin II-induced hypertension accelerates the development of atherosclerosis in apoE-deficient mice","volume":"103","author":"Weiss","year":"2001","journal-title":"Circulation"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3317\/jraas.2001.003","article-title":"Effect of valsartan and captopril in rabbit carotid injury. Possible involvement of bradykinin in the antiproliferative action of the renin-angiotensin blockade","volume":"2","author":"Feng","year":"2001","journal-title":"J. Renin-Angiotensin-Aldosterone Syst."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1161\/01.CIR.90.1.449","article-title":"Potential importance of tissue angiotensin-converting enzyme inhibition in preventing neointima formation","volume":"90","author":"Rakugi","year":"1994","journal-title":"Circulation"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/S0031-6997(24)01471-6","article-title":"Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells","volume":"52","author":"Touyz","year":"2000","journal-title":"Pharmacol. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0167-0115(00)00136-1","article-title":"Reactive oxygen species as mediators of angiotensin II signaling","volume":"91","author":"Griendling","year":"2000","journal-title":"Regul. Pept."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1161\/01.HYP.0000138070.47616.9d","article-title":"Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: What is the clinical significance?","volume":"44","author":"Touyz","year":"2004","journal-title":"Hypertension"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1161\/01.HYP.0000032100.23772.98","article-title":"Role of p47 phox in vascular oxidative stress and hypertension caused by angiotensin II","volume":"40","author":"Landmesser","year":"2002","journal-title":"Hypertension"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4292","DOI":"10.4049\/jimmunol.164.8.4292","article-title":"Crucial role of the amino-terminal tyrosine residue 42 and the carboxyl-terminal PEST domain of I\u03baB\u03b1 in NF-\u03baB activation by an oxidative stress","volume":"164","author":"Schoonbroodt","year":"2000","journal-title":"J. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S0076-6879(10)74016-7","article-title":"Regulation of apoptosis signal-regulating kinase 1 in redox signaling","volume":"Volume 474","author":"Katagiri","year":"2010","journal-title":"Methods in Enzymology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.biocel.2009.11.009","article-title":"Up-regulation of Nrf2-mediated heme oxygenase-1 expression by eckol, a phlorotannin compound, through activation of Erk and PI3K\/Akt","volume":"42","author":"Kim","year":"2010","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S0898-6568(01)00234-0","article-title":"PTEN: The down side of PI 3-kinase signalling","volume":"14","author":"Leslie","year":"2002","journal-title":"Cell. Signal."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1080\/09533710022149395","article-title":"Generation of reactive oxygen species in blood platelets","volume":"13","author":"Wachowicz","year":"2002","journal-title":"Platelets"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/35025229","article-title":"Thrombin signalling and protease-activated receptors","volume":"407","author":"Coughlin","year":"2000","journal-title":"Nature"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.ijsu.2015.08.016","article-title":"Inhibition of reactive oxygen species downregulates the MAPK pathway in rat spinal cord after limb ischemia reperfusion injury","volume":"22","author":"Choi","year":"2015","journal-title":"Int. J. Surg."},{"key":"ref_71","first-page":"45","article-title":"Type 2 diabetes mellitus, oxidative stress and inflammation: Examining the links","volume":"11","author":"Oguntibeju","year":"2019","journal-title":"Int. J. Physiol. Pathophysiol. Pharmacol."},{"key":"ref_72","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_73","doi-asserted-by":"crossref","unstructured":"Burgos-Mor\u00f3n, E., Abad-Jim\u00e9nez, Z., Mart\u00ednez de Mara\u00f1\u00f3n, A., Iannantuoni, F., Escribano-L\u00f3pez, I., L\u00f3pez-Dom\u00e8nech, S., Salom, C., Jover, A., Mora, V., and Roldan, I. (2019). Relationship between oxidative stress, ER stress, and inflammation in type 2 diabetes: The battle continues. J. Clin. Med., 8.","DOI":"10.3390\/jcm8091385"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3734","DOI":"10.1016\/j.febslet.2007.06.044","article-title":"Metabolic stress in insulin\u2019s target cells leads to ROS accumulation\u2013a hypothetical common pathway causing insulin resistance","volume":"581","author":"Eriksson","year":"2007","journal-title":"FEBS Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/0735-1097(96)00206-9","article-title":"Coronary bypass graft fate and patient outcome: Angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years","volume":"28","author":"Fitzgibbon","year":"1996","journal-title":"J. Am. Coll. Cardiol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/159\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T06:00:19Z","timestamp":1768629619000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,15]]},"references-count":75,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cells15020159"],"URL":"https:\/\/doi.org\/10.3390\/cells15020159","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,15]]}}}