{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T13:55:54Z","timestamp":1788184554044,"version":"build-2803163510"},"reference-count":45,"publisher":"Institute of Physiology of the Czech Academy of Sciences","issue":"S1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiol Res"],"abstract":"<jats:p>Iron is an essential mineral participating in numerous biological processes in the organism under physiological conditions. However, it may be also involved in the pathological mechanisms activated in various cardiovascular diseases including myocardial ischemia\/reperfusion (I\/R) injury, due to its involvement in reactive oxygen species (ROS) production. Furthermore, iron has been reported to participate in the mechanisms of iron-dependent cell death defined as \u201cferroptosis\u201d. On the other hand, iron may be also involved in the adaptive processes of ischemic preconditioning (IPC). This study aimed to elucidate whether small amounts of iron may modify the cardiac response to I\/R in isolated perfused rat hearts and their protection by IPC. Pretreatment of the hearts with iron nanoparticles 15 min prior to sustained ischemia (iron preconditioning, Fe-PC) did not attenuate post-I\/R contractile dysfunction. Recovery of left ventricular developed pressure (LVDP) was significantly improved only in the group with combined pretreatment with iron and IPC. Similarly, the rates of contraction and relaxation [+\/-(dP\/dt)max] were almost completely restored in the group preconditioned with a combination of iron and IPC but not with iron alone. In addition, the severity of reperfusion arrhythmias was reduced only in the iron+IPC group. No changes in protein levels of \u201csurvival\u201d kinases of the RISK pathway (Reperfusion Injury Salvage Kinase) were found except for reduced caspase 3 levels in both preconditioned groups. The results indicate that a failure to precondition rat hearts with iron may be associated with the absent upregulation of RISK proteins and the pro-ferroptotic effect manifested by reduced glutathione peroxidase 4 (GPX4) levels. However, combination with IPC suppressed the negative effects of iron resulting in cardioprotection.<\/jats:p>","DOI":"10.33549\/physiolres.935112","type":"journal-article","created":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T13:41:23Z","timestamp":1686145283000},"page":"S61-S72","source":"Crossref","is-referenced-by-count":3,"title":["Effects of Iron Nanoparticles Administration on Ischemia\/Reperfusion Injury in Isolated Hearts of Male Wistar Rats"],"prefix":"10.33549","volume":"72","author":[{"given":"L","family":"KINDERNAY","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"FERENCZYOV\u00c1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V","family":"FARKA\u0160OVA","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"BARTEKOV\u00c1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I","family":"BERN\u00c1TOV\u00c1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"RAVINGEROV\u00c1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19169","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"ref0","doi-asserted-by":"publisher","unstructured":"1.\tHirst J. Mitochondrial complex I. Annu Rev Biochem 2013;82:551-575. https:\/\/doi.org\/10.1146\/annurev-biochem-070511-103700","DOI":"10.1146\/annurev-biochem-070511-103700"},{"key":"ref1","unstructured":"2.\tAbbaspour N, Hurrell R, Kelishadi R. Review on iron and its importance for human health. J Res Med Sci 2014;19:164-174."},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"3.\tvon Haehling S, Ebner N, Evertz R, Ponikowski P, Anker SD. Iron deficiency in heart failure: an overview. JACC Heart Fail 2019;7:36-46. https:\/\/doi.org\/10.1016\/j.jchf.2018.07.015","DOI":"10.1016\/j.jchf.2018.07.015"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"4.\tGonz\u00e1lez-G\u00f3mez MA, Belderbos S, Ya\u00f1ez-Vilar S, Pi\u00f1eiro Y, Cleeren F, Bormans G, Deroose CM, Gsell W, Himmelreich U, Rivas J. Development of superparamagnetic nanoparticles coated with polyacrylic acid and aluminum hydroxide as an efficient contrast agent for multimodal imaging. Nanomaterials (Basel) 2019;9:1626. https:\/\/doi.org\/10.3390\/nano9111626","DOI":"10.3390\/nano9111626"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"5.\tRego GNA, Nucci MP, Mamani JB, Oliveira FA, Marti LC, Filgueiras IS, Ferreira JM, ET AL. Therapeutic efficiency of multiple applications of magnetic hyperthermia technique in glioblastoma using aminosilane coated iron oxide nanoparticles: in vitro and in vivo study. Int J Mol Sci 2020;21:958. https:\/\/doi.org\/10.3390\/ijms21030958","DOI":"10.3390\/ijms21030958"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"6.\tSuk JS, Xu Q, Kim N, Hanes J, Ensign LM. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev 2016;99(Pt A):28-51. https:\/\/doi.org\/10.1016\/j.addr.2015.09.012","DOI":"10.1016\/j.addr.2015.09.012"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"7.\tOleksa V, Bern\u00e1tov\u00e1 I, Patsula V, L\u00ed\u0161kov\u00e1 S, Bali\u0161 P, Rado\u0161insk\u00e1 J, ET AL. Poly(ethylene glycol)-alendronate-coated magnetite nanoparticles do not alter cardiovascular functions and red blood cells' properties in hypertensive rats. Nanomaterials (Basel) 2021;11:1238. https:\/\/doi.org\/10.3390\/nano11051238","DOI":"10.3390\/nano11051238"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"8.\tL\u00ed\u0161kov\u00e1 S, Bali\u0161 P, Mi\u010durov\u00e1 A, Kluknavsk\u00fd M, Okuliarov\u00e1 M, Puzserov\u00e1 A, \u0160kr\u00e1tek M, ET AL. Effect of iron oxide nanoparticles on vascular function and nitric oxide production in acute stress-exposed rats. Physiol Res 2020;69:1067-1083. https:\/\/doi.org\/10.33549\/physiolres.934567","DOI":"10.33549\/physiolres.934567"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"9.\tLaubertova L, Dvorakova M, Balis P, Puzserova A, Zitnanova I, Bernatova I. preliminary findings on the effect of ultrasmall superparamagnetic iron oxide nanoparticles and acute stress on selected markers of oxidative stress in normotensive and hypertensive rats. Antioxidants (Basel) 2022;11:751. https:\/\/doi.org\/10.3390\/antiox11040751","DOI":"10.3390\/antiox11040751"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"10.\tKruszewski M. Labile iron pool: the main determinant of cellular response to oxidative stress. Mutat Res 2003;531:81-92. https:\/\/doi.org\/10.1016\/j.mrfmmm.2003.08.004","DOI":"10.1016\/j.mrfmmm.2003.08.004"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"11.\tValko M, Jomova K, Rhodes CJ, Ku\u010da K, Mus\u00edlek K. Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Arch Toxicol 2016;90:1-37. https:\/\/doi.org\/10.1007\/s00204-015-1579-5","DOI":"10.1007\/s00204-015-1579-5"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"12.\tLi J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, Sun B, Wang G. Ferroptosis: past, present and future. Cell Death Dis 2020;11:88. https:\/\/doi.org\/10.1038\/s41419-020-2298-2","DOI":"10.1038\/s41419-020-2298-2"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"13.\tDixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012;149:1060-1072. https:\/\/doi.org\/10.1016\/j.cell.2012.03.042","DOI":"10.1016\/j.cell.2012.03.042"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"14.\tXie Y, Hou W, Song X, Yu Y, Huang J, Sun X, Kang R, Tang D. Ferroptosis: process and function. Cell Death Differ 2016;23:369-79. https:\/\/doi.org\/10.1038\/cdd.2015.158","DOI":"10.1038\/cdd.2015.158"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"15.\tForcina GC, Dixon SJ. GPX4 at the crossroads of lipid homeostasis and ferroptosis. Proteomics 2019;19:e1800311. https:\/\/doi.org\/10.1002\/pmic.201800311","DOI":"10.1002\/pmic.201800311"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"16.\tFang X, Wang H, Han D, Xie E, Yang X, Wei J, Gu S, ET AL. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci U S A 2019;116:2672-2680. https:\/\/doi.org\/10.1073\/pnas.1821022116","DOI":"10.1073\/pnas.1821022116"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"17.\tRavingerov\u00e1 T, Kindernay L, Bartekov\u00e1 M, Ferko M, Adameov\u00e1 A, Zohdi V, Bern\u00e1tov\u00e1 I, Ferenczyov\u00e1 K, Lazou A. The molecular mechanisms of iron metabolism and its role in cardiac dysfunction and cardioprotection. Int J Mol Sci 2020;21:7889. https:\/\/doi.org\/10.3390\/ijms21217889","DOI":"10.3390\/ijms21217889"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"18.\tBerenshtein E, Vaisman B, Goldberg-Langerman C, Kitrossky N, Konijn AM, Chevion M. Roles of ferritin and iron in ischemic preconditioning of the heart. Mol Cell Biochem 2002;234-235:283-292. https:\/\/doi.org\/10.1023\/A:1015923202082","DOI":"10.1007\/978-1-4615-1087-1_32"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"19.\tMunoz JP, Chiong M, Garc\u00eda L, Troncoso R, Toro B, Pedrozo Z, Diaz-Elizondo J, Salas D, ET AL. Iron induces protection and necrosis in cultured cardiomyocytes: Role of reactive oxygen species and nitric oxide. Free Radic Biol Med 2010;48:526-534. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2009.11.017","DOI":"10.1016\/j.freeradbiomed.2009.11.017"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"20.\tGalleano M, Tapia G, Puntarulo S, Varela P, Videla LA, Fern\u00e1ndez V. Liver preconditioning induced by iron in a rat model of ischemia\/reperfusion. Life Sci 2011;89:221-228. https:\/\/doi.org\/10.1016\/j.lfs.2011.06.005","DOI":"10.1016\/j.lfs.2011.06.005"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"21.\tChevion M, Leibowitz S, Aye NN, Novogrodsky O, Singer A, Avizemer O, Bulvik B, Konijn AM, Berenshtein E. Heart protection by ischemic preconditioning: a novel pathway initiated by iron and mediated by ferritin. J Mol Cell Cardiol 2008;45:839-845. https:\/\/doi.org\/10.1016\/j.yjmcc.2008.08.011","DOI":"10.1016\/j.yjmcc.2008.08.011"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"22.\tBulluck H, Yellon DM, Hausenloy DJ. Reducing myocardial infarct size: challenges and future opportunities. Heart 2016;102:341-348. https:\/\/doi.org\/10.1136\/heartjnl-2015-307855","DOI":"10.1136\/heartjnl-2015-307855"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"23.\tV\u00e9gh A, Parratt JR. The role of mitochondrial K(ATP) channels in antiarrhythmic effects of ischaemic preconditioning in dogs. Br J Pharmacol 2002;137:1107-1115. https:\/\/doi.org\/10.1038\/sj.bjp.0704966","DOI":"10.1038\/sj.bjp.0704966"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"24.\tCave AC. Preconditioning induced protection against post-ischaemic contractile dysfunction: characteristics and mechanisms. J Mol Cell Cardiol 1995;27:969-979. https:\/\/doi.org\/10.1016\/0022-2828(95)90066-7","DOI":"10.1016\/0022-2828(95)90066-7"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"25.\tMatej\u00edkov\u00e1 J, Kucharsk\u00e1 J, Pint\u00e9rov\u00e1 M, Pancza D, Ravingerov\u00e1 T. Protection against ischemia-induced ventricular arrhythmias and myocardial dysfunction conferred by preconditioning in the rat heart: involvement of mitochondrial K(ATP) channels and reactive oxygen species. Physiol Res 2009;58:9-19. https:\/\/doi.org\/10.33549\/physiolres.931317","DOI":"10.33549\/physiolres.931317"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"26.\tHausenloy DJ, Yellon DM. Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection. Heart Fail Rev 2007;12:217-234. https:\/\/doi.org\/10.1007\/s10741-007-9026-1","DOI":"10.1007\/s10741-007-9026-1"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"27.\tJuhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, ET AL. Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 2004;113:1535-1549. https:\/\/doi.org\/10.1172\/JCI19906","DOI":"10.1172\/jci19906"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"28.\tHeusch G. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 2015;116:674-699. https:\/\/doi.org\/10.1161\/CIRCRESAHA.116.305348","DOI":"10.1161\/circresaha.116.305348"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"29.\tBell RM, Mocanu MM, Yellon DM. Retrograde heart perfusion: the Langendorff technique of isolated heart perfusion. J Mol Cell Cardiol 2011;50:940-950. https:\/\/doi.org\/10.1016\/j.yjmcc.2011.02.018","DOI":"10.1016\/j.yjmcc.2011.02.018"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"30.\tWatanabe M, Okada T. Langendorff perfusion method as an ex vivo model to evaluate heart function in rats. Methods Mol Biol 2018;1816:107-116. https:\/\/doi.org\/10.1007\/978-1-4939-8597-5_8","DOI":"10.1007\/978-1-4939-8597-5_8"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"31.\tWalker MJ, Curtis MJ, Hearse DJ, Campbell RW, Janse MJ, Yellon DM, Cobbe SM, ET AL. The Lambeth Conventions: guidelines for the study of arrhythmias in ischaemia infarction, and reperfusion. Cardiovasc Res 1988;22:447-455. https:\/\/doi.org\/10.1093\/cvr\/22.7.447","DOI":"10.1093\/cvr\/22.7.447"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"32.\tCurtis MJ, Walker MJ. Quantification of arrhythmias using scoring systems: an examination of seven scores in an in vivo model of regional myocardial ischaemia. Cardiovasc Res 1988;22:656-665. https:\/\/doi.org\/10.1093\/cvr\/22.9.656","DOI":"10.1093\/cvr\/22.9.656"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"33.\tBradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248-254. https:\/\/doi.org\/10.1016\/0003-2697(76)90527-3","DOI":"10.1016\/0003-2697(76)90527-3"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"34.\tChevion M, Jiang Y, Har-El R, Berenshtein E, Uretzky G, Kitrossky N. Copper and iron are mobilized following myocardial ischemia: possible predictive criteria for tissue injury. Proc Natl Acad Sci U S A 1993;90:1102-1106. https:\/\/doi.org\/10.1073\/pnas.90.3.1102","DOI":"10.1073\/pnas.90.3.1102"},{"key":"ref34","unstructured":"35.\tKramer JH, Lightfoot FG, Weglicki WB. Cardiac tissue iron: effects on post-ischemic function and free radical production, and its possible role during preconditioning. Cell Mol Biol (Noisy-le-grand) 2000;46:1313-1327."},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"36.\tLesnefsky EJ, Chen Q, Tandler B, Hoppel CL. Mitochondrial dysfunction and myocardial ischemia-reperfusion: implications for novel therapies. Annu Rev Pharmacol Toxicol 2017;57:535-565. https:\/\/doi.org\/10.1146\/annurev-pharmtox-010715-103335","DOI":"10.1146\/annurev-pharmtox-010715-103335"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"37.\tChan S, Lian Q, Chen M-P, Jiang D, Ho JTK, Cheung Y-F, Chan GC-F. Deferiprone inhibits iron overload-induced tissue factor bearing endothelial microparticle generation by inhibition oxidative stress induced mitochondrial injury, and apoptosis. Toxicol Appl Pharmacol 2018;338:148-158. https:\/\/doi.org\/10.1016\/j.taap.2017.11.005","DOI":"10.1016\/j.taap.2017.11.005"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"38.\tLecour S. Activation of the protective Survivor Activating Factor Enhancement (SAFE) pathway against reperfusion injury: Does it go beyond the RISK pathway? J Mol Cell Cardiol 2009;47:32-40. https:\/\/doi.org\/10.1016\/j.yjmcc.2009.03.019","DOI":"10.1016\/j.yjmcc.2009.03.019"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"39.\tLecour S, Suleman N, Deuchar GA, Somers S, Lacerda L, Huisamen B, Opie LH. Pharmacological preconditioning with tumor necrosis factor-alpha activates signal transducer and activator of transcription-3 at reperfusion without involving classic prosurvival kinases (Akt and extracellular signal-regulated kinase). Circulation 2005;112:3911-3918. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.105.581058","DOI":"10.1161\/circulationaha.105.581058"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"40.\tSuleman N, Somers S, Smith R, Opie LH, Lecour SC. Dual activation of STAT-3 and Akt is required during the trigger phase of ischaemic preconditioning. Cardiovasc Res 2008;79:127-133. https:\/\/doi.org\/10.1093\/cvr\/cvn067","DOI":"10.1093\/cvr\/cvn067"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"41.\tStockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, ET AL. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017;171:273-285. https:\/\/doi.org\/10.1016\/j.cell.2017.09.021","DOI":"10.1016\/j.cell.2017.09.021"},{"key":"ref41","unstructured":"42.\tAndelov\u00e1 E, Bartekov\u00e1 M, Pancza D, Styk J, Ravingerov\u00e1 T. The role of NO in ischemia\/reperfusion injury in isolated rat heart. Gen Physiol Biophys 2005;24:411-426."},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"43.\tGriecsov\u00e1 L, Farka\u0161ov\u00e1 V, G\u00e1blovsk\u00fd I, Khandelwal VK, Bern\u00e1tov\u00e1 I, Tatarkov\u00e1 Z, Kaplan P, Ravingerov\u00e1 T. Effect of maturation on the resistance of rat hearts against ischemia. Study of potential molecular mechanisms. Physiol Res 2015;64(Suppl 5):S685-S696. https:\/\/doi.org\/10.33549\/physiolres.933222","DOI":"10.33549\/physiolres.933222"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"44.\tLonek L, Puhova A, Griecsova-Kindernay L, Patel SP, Zohdi V, Jezova D, Ravingerova T. Voluntary exercise may activate components of pro-survival risk pathway in the rat heart and potentially modify cell proliferation in the myocardium. Physiol Res 2019;68:581-588. https:\/\/doi.org\/10.33549\/physiolres.934182","DOI":"10.33549\/physiolres.934182"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"45.\tKindernay L, Farkasova V, Neckar J, Hrdlicka J, Ytrehus K, Ravingerova T. Impact of maturation on myocardial response to ischemia and the effectiveness of remote preconditioning in male rats. Int J Mol Sci 2021;22:11009. https:\/\/doi.org\/10.3390\/ijms222011009","DOI":"10.3390\/ijms222011009"}],"container-title":["Physiological Research"],"original-title":[],"language":"en","deposited":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T13:41:34Z","timestamp":1686145294000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.biomed.cas.cz\/physiolres\/pdf\/2023\/72_S61.pdf"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,31]]},"references-count":45,"journal-issue":{"issue":"S1","published-online":{"date-parts":[[2023,5,31]]}},"URL":"https:\/\/doi.org\/10.33549\/physiolres.935112","relation":{},"ISSN":["1802-9973","0862-8408"],"issn-type":[{"value":"1802-9973","type":"electronic"},{"value":"0862-8408","type":"print"}],"subject":[],"published":{"date-parts":[[2023,5,31]]}}}