ABSTRACT
Transferrin receptor 2 (Tfr2) is an iron-modulator transcribed in two isoforms, Tfr2α and Tfr2ß. The latter is expressed in the heart. We obtained two mouse models with silencing of Tfr2ß: 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 Tfr2ß might play a role in myocardial injury and whether Tfr2ß 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. Tfr2ß increased in WT hearts subject to I/R, and both Tfr2ß 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 GSK3ß resulted phosphorylated during I/R in LCKO-KI hearts. While HO-1 and HIF-2a were high in both Tfr2ß-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, Tfr2ß 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 Tfr2ß downregulation and subsequent Ferritins upregulation.
Subject(s)
Myocardial Ischemia/metabolism , Myocardium/metabolism , Receptors, Transferrin/metabolism , Animals , Male , Mice , Mice, Knockout , Mice, Transgenic , Myocardial Ischemia/genetics , Myocardial Reperfusion , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptors, Transferrin/geneticsABSTRACT
We studied by immunohistochemistry the background CD20 + cells in 131 cases of classical Hodgkin lymphoma (cHL). High CD20 + dispersed cells (CD20BG) showed a significant correlation with longer overall survival (OS) and a trend toward improved progression-free survival (PFS). At multivariate analysis high CD20BG was also an independent prognostic factor of improved PFS and OS. The prognostic role of CD20BG seems to be opposite with respect to tumor associated macrophages (TAMs) we studied previously in most cases of the series. We scored patients on the basis of the respective CD20BG and TAM count and found that the combination of low CD20BG and high TAMs was related to a significantly reduced PFS and OS at univariate and multivariate analysis. Microenvironment CD20 + cells seem to play a favorable prognostic role in cHL. Depletion of CD20 + cells together with an increase of TAMs identifies a group of patients with high-risk disease.
