{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T15:51:47Z","timestamp":1771602707141,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T00:00:00Z","timestamp":1628726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001870","name":"Fundacja na rzecz Nauki Polskiej","doi-asserted-by":"publisher","award":["application 0016"],"award-info":[{"award-number":["application 0016"]}],"id":[{"id":"10.13039\/501100001870","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005632","name":"Narodowe Centrum Bada\u0144 i Rozwoju","doi-asserted-by":"publisher","award":["STRATEGMED1\/233226\/11\/NCBR\/2015"],"award-info":[{"award-number":["STRATEGMED1\/233226\/11\/NCBR\/2015"]}],"id":[{"id":"10.13039\/501100005632","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Angiotensin II (Ang II) induces hypertension and endothelial dysfunction, but the involvement of thrombin in these responses is not clear. Here, we assessed the effects of the inhibition of thrombin activity by dabigatran on Ang II-induced hypertension and endothelial dysfunction in mice with a particular focus on NO- and 20-HETE-dependent pathways. As expected, dabigatran administration significantly delayed thrombin generation (CAT assay) in Ang II-treated hypertensive mice, and interestingly, it prevented endothelial dysfunction development, but it did not affect elevated blood pressure nor excessive aortic wall thickening. Dabigatran\u2019s effects on endothelial function in Ang II-treated mice were evidenced by improved NO-dependent relaxation in the aorta in response to acetylcholine in vivo (MRI measurements) and increased systemic NO bioavailability (NO2\u2212 quantification) with a concomitant increased ex vivo production of endothelium-derived NO (EPR analysis). Dabigatran treatment also contributed to the reduction in the endothelial expression of pro-inflammatory vWF and ICAM-1. Interestingly, the fall in systemic NO bioavailability in Ang II-treated mice was associated with increased 20-HETE concentration in plasma (UPLC-MS\/MS analysis), which was normalised by dabigatran treatment. Taking together, the inhibition of thrombin activity in Ang II-induced hypertension in mice improves the NO-dependent function of vascular endothelium and normalises the 20-HETE-depedent pathway without affecting the blood pressure and vascular remodelling.<\/jats:p>","DOI":"10.3390\/ijms22168664","type":"journal-article","created":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T10:54:41Z","timestamp":1628765681000},"page":"8664","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Thrombin Inhibition Prevents Endothelial Dysfunction and Reverses 20-HETE Overproduction without Affecting Blood Pressure in Angiotensin II-Induced Hypertension in Mice"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2233-0564","authenticated-orcid":false,"given":"Agnieszka","family":"Kij","sequence":"first","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0182-6501","authenticated-orcid":false,"given":"Anna","family":"Bar","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8526-945X","authenticated-orcid":false,"given":"Kamil","family":"Przyborowski","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5138-1451","authenticated-orcid":false,"given":"Bartosz","family":"Proniewski","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lukasz","family":"Mateuszuk","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnieszka","family":"Jasztal","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5447-0812","authenticated-orcid":false,"given":"Anna","family":"Kieronska-Rudek","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brygida","family":"Marczyk","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2538-6766","authenticated-orcid":false,"given":"Karolina","family":"Matyjaszczyk-Gwarda","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0638-9008","authenticated-orcid":false,"given":"Anna","family":"Tworzydlo","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilla","family":"Enggaard","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Renal Research, University of Southern Denmark, J.B. Winsl\u00f8ws Vej 21, 5000 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pernille B. L\u00e6rkegaard","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Renal Research, University of Southern Denmark, J.B. Winsl\u00f8ws Vej 21, 5000 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boye","family":"Jensen","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Renal Research, University of Southern Denmark, J.B. 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Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1161\/CIRCULATIONAHA.106.652859","article-title":"Endothelial function and dysfunction: Testing and clinical relevance","volume":"115","author":"Deanfield","year":"2007","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"351","DOI":"10.2217\/bmm.10.61","article-title":"Endothelial function as a functional expression of cardiovascular risk factors","volume":"4","author":"Reriani","year":"2010","journal-title":"Biomark. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"598271","DOI":"10.1155\/2014\/598271","article-title":"Endothelial dysfunction in experimental models of arterial hypertension: Cause or consequence?","volume":"2014","author":"Bernatova","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1093\/bjaceaccp\/mkh020","article-title":"Hypertension: Pathophysiology and treatment","volume":"4","author":"Sear","year":"2004","journal-title":"Contin. Educ. Anaesthesia Crit. Care Pain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.5455\/msm.2017.29.35-39","article-title":"Population attributable fraction for cardiovascular diseases risk factors in selected countries: A comparative study","volume":"29","author":"Pirani","year":"2017","journal-title":"Mater. Socio Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"592","DOI":"10.3389\/fphys.2017.00592","article-title":"A single angiotensin II hypertensive stimulus is associated with prolonged neuronal and immune system activation in Wistar-Kyoto rats","volume":"8","author":"Zubcevic","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.2741\/4465","article-title":"Molecular mechanisms and cell signaling of 20-hydroxyeicosatetraenoic acid in vascular pathophysiology","volume":"21","author":"Fan","year":"2016","journal-title":"Front. Biosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1161\/HYPERTENSIONAHA.110.154559","article-title":"CYP4A2-induced hypertension is 20-hydroxyeicosatetraenoic acid- and angiotensin II-dependent","volume":"56","author":"Sodhi","year":"2010","journal-title":"Hypertension"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.tcm.2007.11.002","article-title":"Vascular cytochrome P450 enzymes: Physiology and pathophysiology","volume":"18","author":"Fleming","year":"2008","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"eaah4923","DOI":"10.1126\/scitranslmed.aah4923","article-title":"Platelet-localized FXI promotes a vascular coagulation-inflammatory circuit in arterial hypertension","volume":"9","author":"Kossmann","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"106632","DOI":"10.1016\/j.vph.2019.106632","article-title":"Thrombin inhibition by dabigatran attenuates endothelial dysfunction in diabetic mice","volume":"124","author":"Rahadian","year":"2020","journal-title":"Vascul. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hasan, H., Park, S.-H., Auger, C., Belcastro, E., Matsushita, K., Marchandot, B., Lee, H.-H., Qureshi, A., Kauffenstein, G., and Ohlmann, P. (2019). Thrombin induces angiotensin II-mediated senescence in atrial endothelial cells: Impact on pro-remodeling patterns. J. Clin. Med., 8.","DOI":"10.3390\/jcm8101570"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12959-019-0194-8","article-title":"Protease-activated receptors (PARs): Mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases","volume":"17","author":"Heuberger","year":"2019","journal-title":"Thromb. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"18412","DOI":"10.1074\/jbc.M114.628156","article-title":"Endothelial angiogenesis and barrier function in response to thrombin require Ca2+ influx through the Na+\/Ca2+exchanger","volume":"290","author":"Andrikopoulos","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1182\/blood.V92.4.1259","article-title":"Thrombin-activated human endothelial cells support monocyte adhesion in vitro following expression of intercellular adhesion molecule-1 (ICAM-1; CD54) and vascular cell adhesion molecule-1 (VCAM-1; CD106)","volume":"92","author":"Kaplanski","year":"1998","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"396","DOI":"10.3389\/fphys.2014.00396","article-title":"Angiotensin II-induced endothelial dysfunction is temporally linked with increases in interleukin-6 and vascular macrophage accumulation","volume":"5","author":"Gomolak","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1161\/CIRCULATIONAHA.111.034470","article-title":"Lysozyme M-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction","volume":"124","author":"Wenzel","year":"2011","journal-title":"Circulation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1161\/ATVBAHA.113.301437","article-title":"Angiotensin II-induced vascular dysfunction depends on interferon-\u03b3- driven immune cell recruitment and mutual activation of monocytes and NK-cells","volume":"33","author":"Kossmann","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_20","first-page":"6721531","article-title":"T cell-derived IL-17A induces vascular dysfunction via perivascular fibrosis formation and dysregulation of\u00b7NO\/cGMP signaling","volume":"2019","author":"Efentakis","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1126\/science.1084183","article-title":"Modulation of \u03b1-thrombin function by distinct interactions with platelet glycoprotein Ib\u03b1","volume":"301","author":"Celikel","year":"2003","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1084\/jem.192.2.193","article-title":"Platelet glycoprotein Ib\u03b1 is a counterreceptor for the leukocyte integrin Mac-1 (CD11b\/CD18)","volume":"192","author":"Simon","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.thromres.2018.11.027","article-title":"Enhanced thrombin generation in patients with arterial hypertension","volume":"174","author":"Elias","year":"2019","journal-title":"Thromb. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1159\/000452269","article-title":"Protease-activated receptor 1 contributes to angiotensin II-induced cardiovascular remodeling and inflammation","volume":"136","author":"Antoniak","year":"2017","journal-title":"Cardiology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41598-017-00473-5","article-title":"Angiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice","volume":"7","author":"Yang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"528757","DOI":"10.1155\/2015\/528757","article-title":"Animal models in cardiovascular research: Hypertension and atherosclerosis","volume":"2015","author":"Leong","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"653","DOI":"10.3892\/br.2016.784","article-title":"Animal models for the study of primary and secondary hypertension in humans","volume":"5","author":"Lin","year":"2016","journal-title":"Biomed. Reports."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1139\/y97-176","article-title":"Receptor-activating peptides distinguish thrombin receptor (PAR-1) and protease activated receptor 2 (PAR-2) mediated hemodynamic responses in vivo","volume":"76","author":"Cheung","year":"1998","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e015616","DOI":"10.1161\/JAHA.119.015616","article-title":"Blockade of PAR-1 signaling attenuates cardiac hypertrophy and fibrosis in renin-overexpressing hypertensive mice","volume":"9","author":"Yokono","year":"2020","journal-title":"J. Am. Heart. Assoc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1161\/01.RES.80.6.838","article-title":"Vascular thrombin receptor regulation in hypertensive rats","volume":"80","author":"Capers","year":"1997","journal-title":"Circ. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e011171","DOI":"10.1161\/JAHA.118.011171","article-title":"Degradation of glycocalyx and multiple manifestations of endothelial dysfunction coincide in the early phase of endothelial dysfunction before atherosclerotic plaque development in apolipoprotein E\/low-density lipoprotein receptor-deficient mice","volume":"8","author":"Bar","year":"2019","journal-title":"J. Am. Heart. Assoc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e016929","DOI":"10.1161\/JAHA.120.016929","article-title":"In vivo magnetic resonance imaging-based detection of heterogeneous endothelial response in thoracic and abdominal aorta to short-term high-fat diet ascribed to differences in perivascular adipose tissue in mice","volume":"9","author":"Bar","year":"2020","journal-title":"J. Am. Heart. Assoc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1161\/ATVBAHA.112.248344","article-title":"Induction of angiotensin-converting enzyme and activation of the renin-angiotensin system contribute to 20-hydroxyeicosatetraenoic acid-mediated endothelial dysfunction","volume":"32","author":"Cheng","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1161\/HYPERTENSIONAHA.107.105395","article-title":"Altered release of cytochrome P450 metabolites of arachidonic acid in renovascular disease","volume":"51","author":"Minuz","year":"2008","journal-title":"Hypertension"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.pharmthera.2018.07.004","article-title":"20-HETE in the regulation of vascular and cardiac function","volume":"192","author":"Rocic","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.prostaglandins.2011.06.006","article-title":"The role of 20-HETE in androgen-mediated hypertension","volume":"96","author":"Wu","year":"2011","journal-title":"Prostaglandins Other. Lipid Mediat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1016\/j.bbadis.2019.05.021","article-title":"5-Lipoxagenase deficiency attenuates L-NAME-induced hypertension and vascular remodeling","volume":"1865","author":"Chen","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1086\/686311","article-title":"Plasma 12- and 15-hydroxyeicosanoids are predictors of survival in pulmonary arterial hypertension","volume":"6","author":"Sagliani","year":"2016","journal-title":"Pulm. Circ."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1161\/hy0202.103788","article-title":"Soluble epoxide hydrolase inhibition lowers arterial blood pressure in angiotensin II hypertension","volume":"39","author":"Imig","year":"2002","journal-title":"Hypertension"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1161\/01.HYP.0000153792.29478.1d","article-title":"Soluble epoxide hydrolase is a main effector of angiotensin II-induced hypertension","volume":"45","author":"Jung","year":"2005","journal-title":"Hypertension"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"E691","DOI":"10.1152\/ajpendo.00710.2010","article-title":"Soluble epoxide hydrolase in the generation and maintenance of high blood pressure in spontaneously hypertensive rats","volume":"300","author":"Koeners","year":"2011","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"118474","DOI":"10.1016\/j.lfs.2020.118474","article-title":"Influence of dabigatran on pro-inflammatory cytokines; growth factors and chemokines\u2013Slowing the vicious circle of coagulation and inflammation","volume":"262","author":"Paar","year":"2020","journal-title":"Life Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3216","DOI":"10.1096\/fj.201500163R","article-title":"MicroRNA-181b inhibits thrombin-mediated endothelial activation and arterial thrombosis by targeting caspase recruitment domain family member 10","volume":"30","author":"Lin","year":"2016","journal-title":"FASEB J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1172\/JCI118074","article-title":"Nitric oxide decreases cytokine-induced endothelial activation: Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines","volume":"96","author":"Libby","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/bs.apha.2016.04.003","article-title":"Epoxyeicosatrienoic acids and 20-hydroxyeicosatetraenoic acid on endothelial and vascular function","volume":"77","author":"Imig","year":"2016","journal-title":"Adv. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Laursen, S.B., Finsen, S., Marcussen, N., Quaggin, S.E., Hansen, B.L., and Dimke, H. (2018). Endothelial mineralocorticoid receptor ablation does not alter blood pressure; kidney function or renal vessel contractility. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193032"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1111\/j.1538-7836.2007.02719.x","article-title":"Development of a calibrated automated thrombography based thrombin generation test in mouse plasma","volume":"5","author":"Tchaikovski","year":"2007","journal-title":"J. Thromb. Haemost."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.thromres.2012.10.011","article-title":"Data management in thrombin generation","volume":"131","author":"Hemker","year":"2013","journal-title":"Thromb. Res."},{"key":"ref_49","first-page":"1926","article-title":"Breast cancer pulmonary metastasis is increased in mice undertaking spontaneous physical training in the running wheel; a call for revising beneficial effects of exercise on cancer progression","volume":"7","author":"Smeda","year":"2017","journal-title":"Am. J. Cancer. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.jpba.2016.06.050","article-title":"Simultaneous quantification of PGI2 and TXA2 metabolites in plasma and urine in NO-deficient mice by a novel UHPLC\/MS\/MS method","volume":"129","author":"Kij","year":"2016","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1007\/s00418-017-1538-8","article-title":"Combined orcein and martius scarlet blue (OMSB) staining for qualitative and quantitative analyses of atherosclerotic plaques in brachiocephalic arteries in apoE\/LDLR\u2212\/\u2212 mice","volume":"147","author":"Gajda","year":"2017","journal-title":"Histochem. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1080\/09537104.2016.1254764","article-title":"Effects of a single bout of strenuous exercise on platelet activation in female ApoE\/LDLR\u2212\/\u2212 mice","volume":"28","author":"Przyborowski","year":"2017","journal-title":"Platelets"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.biochi.2020.03.010","article-title":"Development and validation of a rapid; specific and sensitive LC-MS\/MS bioanalytical method for eicosanoid quantification-assessment of arachidonic acid metabolic pathway activity in hypertensive rats","volume":"171\u2013172","author":"Kij","year":"2020","journal-title":"Biochimie"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1002\/elps.201300450","article-title":"Simultaneous analysis of reduced glutathione and glutathione disulfide by capillary zone electrophoresis","volume":"35","author":"Hempe","year":"2014","journal-title":"Electrophoresis"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8664\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:44:47Z","timestamp":1760165087000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8664"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,12]]},"references-count":54,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22168664"],"URL":"https:\/\/doi.org\/10.3390\/ijms22168664","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,12]]}}}