title: T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Sirinart
authors.initials: S
authors.lastname: Kumfu
authors.forename: Siriporn
authors.initials: S
authors.lastname: Chattipakorn
authors.forename: Kroekkiat
authors.initials: K
authors.lastname: Chinda
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.forename: Nipon
authors.initials: N
authors.lastname: Chattipakorn
mesh_terms: D000818:Animals; D001393:Azoles / Q000627:therapeutic use; D001483:Base Sequence; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000235:genetics; D002319:Cardiovascular System / Q000187:drug effects / Q000503:physiopathology; D017931:DNA Primers / Q000235:genetics; D003676:Deferoxamine / Q000627:therapeutic use; D004095:Dihydropyridines / Q000627:therapeutic use; D004195:Disease Models, Animal; D006339:Heart Rate; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism; D007502:Iron Chelating Agents / Q000627:therapeutic use; D019266:Iron, Dietary / Q000008:administration & dosage; D054833:Isoindoles; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009543:Nifedipine / Q000627:therapeutic use; D009596:Nitrophenols / Q000627:therapeutic use; D009929:Organ Size / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000627:therapeutic use; D016566:Organoselenium Compounds / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D014700:Verapamil / Q000627:therapeutic use; D017086:beta-Thalassemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
chemical_list: D001393:Azoles; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D017931:DNA Primers; D004095:Dihydropyridines; D007502:Iron Chelating Agents; D019266:Iron, Dietary; D054833:Isoindoles; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D016566:Organoselenium Compounds; D012333:RNA, Messenger; C042986:ebselen; C066425:efonidipine; D014700:Verapamil; D007501:Iron; D009543:Nifedipine; D003676:Deferoxamine