title: A comparative study of myocardial molecular phenotypes of two tfr2β null mice: role in ischemia/reperfusion.
abstract: Transferrin receptor 2 (Tfr2) is an iron-modulator transcribed in two isoforms, Tfr2α and Tfr2β. The latter is expressed in the heart. We obtained two mouse models with silencing of Tfr2β: one with a normal systemic iron amount (SIA), i.e., Tfr2-KI, and the other, i.e., LCKO-KI, with high SIA due to hepatic Tfr2α silencing. We aimed to assess whether Tfr2β might play a role in myocardial injury and whether Tfr2β silencing might modify proteins of iron metabolism, antioxidant, apoptotic, and survival enzyme activities in the heart undergoing ischemia/reperfusion (I/R). Isolated hearts of wild-type (WT) and Tfr2-null mice were studied before or after an I/R protocol, and proteins/RNA analyzed by Western blot and/or quantitative PCR. Tfr2β increased in WT hearts subject to I/R, and both Tfr2β null mice hearts were protected against I/R injury (about 40% smaller infarct-size compared to WT hearts). RISK kinases (ERK1/2-AKT-PKCε) were found up-regulated after I/R in Tfr2-KI, whereas SAFE enzyme (Stat3) and GSK3β resulted phosphorylated during I/R in LCKO-KI hearts. While HO-1 and HIF-2a were high in both Tfr2β-null mice, Catalase, and proapoptotic factors were upregulated only in LCKO-KI. Finally, Tfr2-KI hearts presented an increased Ferritin-H and a decreased Ferroportin1, whereas LCKO-KI hearts displayed an upregulation of Ferritin-L chain and DMT1/Hamp-RNA. In conclusion, Tfr2β isoform is involved in cardiac iron metabolism and its silencing leads to a protected phenotype (antioxidants, RISK, and/or SAFE upregulation) against I/R challenging. Iron-dependent signals involved in cardioprotection seem to be positively affected by Tfr2β downregulation and subsequent Ferritins upregulation.
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, AOU San Luigi Gonzaga, Orbassano, Torino, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Boero
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, AOU San Luigi Gonzaga, Orbassano, Torino, Italy.|Cardiovascular Physiology Lab (Torino), National Institute for Cardiovascular Researches (INRC), Bologna, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pagliaro
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, AOU San Luigi Gonzaga, Orbassano, Torino, Italy.|Cardiovascular Physiology Lab (Torino), National Institute for Cardiovascular Researches (INRC), Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tullio
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, AOU San Luigi Gonzaga, Orbassano, Torino, Italy.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Pellegrino
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, AOU San Luigi Gonzaga, Orbassano, Torino, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Palmieri
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, AOU San Luigi Gonzaga, Orbassano, Torino, Italy.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Ferbo
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, AOU San Luigi Gonzaga, Orbassano, Torino, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, AOU San Luigi Gonzaga, Orbassano, Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: De Gobbi
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, AOU San Luigi Gonzaga, Orbassano, Torino, Italy.|Cardiovascular Physiology Lab (Torino), National Institute for Cardiovascular Researches (INRC), Bologna, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Penna
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, AOU San Luigi Gonzaga, Orbassano, Torino, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Roetto
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D011990:Receptors, Transferrin; C503641:TFR2 protein, mouse
keywords: RISK; SAFE; ferritin; iron; transferrin receptor; transgenic model