nitrophenols and ebselen

Iron-overload cardiomyopathy is a major cause of death in thalassemic patients. However, pathways of non-transferrin-bound iron (NTBI) uptake into cardiomyocytes under iron-overload conditions are still controversial. We previously demonstrated that Fe(2+) uptake in thalassemic cardiomyocytes is mainly mediated by T-type calcium channels (TTCCs). However, direct evidence regarding Fe(3+) uptake, the other form of NTBI, in thalassemic cardiomyocytes has never been investigated. Hearts from genetic-altered β-thalassemic mice and adult wild-type (WT) mice were used for cultured ventricular cardiomyocytes. Blockers for L-type calcium channel (LTCC), TTCC, transferrin receptor1 (TfR1), and divalent metal transporter1 (DMT1) were used, and quantification of cellular iron uptake was performed by the acetoxymethyl ester of calcein fluorescence assay. Cellular uptake of Fe(3+) under iron-overload conditions in cultured ventricular myocytes of thalassemic mice was greater than that of WT cells (P < 0.01). The iron chelator, deferoxamine, could prevent Fe(3+) uptake into cultured cardiomyocytes. However, blockers of TfR1, DMT1, LTCC, and TTCC could not prevent Fe(3+) uptake into cardiomyocytes. Our findings indicated that, unlike Fe(2+), Fe(3+) uptake in cultured thalassemic cardiomyocytes is not mainly mediated by TfR1, DMT1, LTCC, and TTCC, suggesting that another alternative pathway could play a major role in Fe(3+) uptake in thalassemic cardiomyocytes.

Topics: Animals; Azoles; beta-Thalassemia; Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Calcium Channels, T-Type; Cation Transport Proteins; Cell Survival; Cells, Cultured; Deferoxamine; Dihydropyridines; Disease Models, Animal; Ferric Compounds; Heart Ventricles; Iron Overload; Isoindoles; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Nitrophenols; Organophosphorus Compounds; Organoselenium Compounds; Quaternary Ammonium Compounds; Receptors, Transferrin; Verapamil

Iron-overload cardiomyopathy is a major cause of morbidity and mortality in patients with thalassemia. However, the precise mechanisms of iron entry and sequestration in the heart are still unclear. Our previous study showed that Fe(2+) uptake in thalassemic cardiomyocytes are mainly mediated by T-type calcium channels (TTCC). Nevertheless, the role of TTCC as well as other transporters such as divalent metal transporter1 (DMT1) and L-type calcium channels (LTCC) as possible portals for iron entry into the heart in in vivo thalassemic mice under an iron-overload condition has not been investigated.. An iron-overload condition was induced in genetically altered β-thalassemic mice and adult wild-type mice by feeding them with an iron diet (0.2% ferrocene w/w) for 3 months. Then, blockers for LTCC (verapamil and nifedipine), TTCC (efonidipine), and DMT1 (ebselen) as well as iron chelator desferoxamine (DFO) were given for 1 month with continuous iron feeding.. Treatment with LTCC, TTCC, DMT1 blockers, and DFO reduced cardiac iron deposit, cardiac malondialdehyde (MDA), plasma non-transferrin-bound iron, and improved heart rate variability and left ventricular (LV) function in thalassemic mice with iron overload. Only TTCC and DMT1 blockers and DFO reduced liver iron accumulation, liver MDA, plasma MDA, and decreased mortality rate in iron-overloaded thalassemic mice.. DMT1, LTCC, and TTCC played important roles for iron entry in the thalassemic heart under an iron-overloaded condition. Unlike LTCC blocker, TTCC blocker provided all benefits including attenuating iron deposit in both the heart and liver, reduced oxidative stress, and decreased mortality in iron-overloaded mice.

Topics: Animals; Azoles; Base Sequence; beta-Thalassemia; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Cardiovascular System; Deferoxamine; Dihydropyridines; Disease Models, Animal; DNA Primers; Heart Rate; Humans; Iron; Iron Chelating Agents; Iron, Dietary; Isoindoles; Mice; Mice, Inbred C57BL; Mice, Knockout; Nifedipine; Nitrophenols; Organ Size; Organophosphorus Compounds; Organoselenium Compounds; RNA, Messenger; Ventricular Function, Left; Verapamil