title: Effects of iron overload, an iron chelator and a T-Type calcium channel blocker on cardiac mitochondrial biogenesis and mitochondrial dynamics in thalassemic mice.
abstract: Although cardiac mitochondrial dysfunction is involved in the pathophysiology of iron-overload cardiomyopathy, the precise mechanisms of iron-induced mitochondrial dysfunction, and the roles of the iron chelator deferiprone and the T-type calcium channel blocker efonidipine on cardiac mitochondrial biogenesis in thalassemic mice are still unknown. β-thalassemic (HT) mice were fed with a normal diet (ND) or a high iron-diet (FE) for 90 days. Then, the FE-fed mice were treated with deferiprone (75mg/kg/day) or efonidipine (4mg/kg/day) for 30 days. The hearts were used to determine cardiac mitochondrial function, biogenesis, mitochondrial dynamics and protein expressions for oxidative phosphorylation (OXPHOS) and apoptosis. ND-fed HT mice had impaired heart rate variability (HRV), increased mitochondrial dynamic proteins and caspase-3, compared with ND-fed wild-type mice. Iron overload led to increased plasma non-transferrin bound iron, oxidative stress, and the impairments of HRV and left ventricular function, cardiac mitochondrial function and mitochondrial dynamics, and decreased complex IV in thalassemic mice. Our results suggested that deferiprone and efonidipine treatment showed similar benefit in attenuating cardiac iron deposit and oxidative stress, and improved cardiac mitochondrial function, leading to improved left ventricular function, without altering the cardiac mitochondrial biogenesis, and apoptosis proteins in iron-overload thalassemic mice.
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Juthamas
authors.initials: J
authors.lastname: Khamseekaew
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Sirinart
authors.initials: S
authors.lastname: Kumfu
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Suwakon
authors.initials: S
authors.lastname: Wongjaikam
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Sasiwan
authors.initials: S
authors.lastname: Kerdphoo
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Thidarat
authors.initials: T
authors.lastname: Jaiwongkam
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Somdet
authors.initials: S
authors.lastname: Srichairatanakool
authors.affiliation: Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand.
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Siriporn C
authors.initials: SC
authors.lastname: Chattipakorn
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand. Electronic address: nchattip@gmail.com.
authors.forename: Nipon
authors.initials: N
authors.lastname: Chattipakorn
mesh_terms: D000628:Aminophylline; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001285:Atropine; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D000077543:Deferiprone; D004095:Dihydropyridines / Q000494:pharmacology* / Q000627:therapeutic use; D004338:Drug Combinations; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D007501:Iron / Q000097:blood; D007502:Iron Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use; D019190:Iron Overload / Q000150:complications*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D005996:Nitroglycerin; D009596:Nitrophenols / Q000494:pharmacology* / Q000627:therapeutic use; D001678:Organelle Biogenesis; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010208:Papaverine; D010634:Phenobarbital; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013789:Thalassemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D004095:Dihydropyridines; D004338:Drug Combinations; D007502:Iron Chelating Agents; C026863:Myocardon; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D011728:Pyridones; D000628:Aminophylline; D000077543:Deferiprone; C066425:efonidipine; D008315:Malondialdehyde; D001285:Atropine; D010208:Papaverine; D007501:Iron; D005996:Nitroglycerin; D010634:Phenobarbital
keywords: Cardiomyopathy; Deferiprone (PubChem CID: 2972); Efonidipine (PubChem CID: 163838); Iron overload; Mitochondrial dynamics; Oxidative phosphorylation; Thalassemic mice