title: Mitochondrial transporter ATP binding cassette mitochondrial erythroid is a novel gene required for cardiac recovery after ischemia/reperfusion.
abstract: BACKGROUND
  Oxidative stress and mitochondrial dysfunction are central mediators of cardiac dysfunction after ischemia/reperfusion. ATP binding cassette mitochondrial erythroid (ABC-me; ABCB10; mABC2) is a mitochondrial transporter highly induced during erythroid differentiation and predominantly expressed in bone marrow, liver, and heart. Until now, ABC-me function in heart was unknown. Several lines of evidence demonstrate that the yeast ortholog of ABC-me protects against increased oxidative stress. Therefore, ABC-me is a potential modulator of the outcome of ischemia/reperfusion in the heart.
  
  
  RESULTS
  Mice harboring 1 functional allele of ABC-me (ABC-me(+/-)) were generated by replacing ABC-me exons 2 and 3 with a neomycin resistance cassette. Cardiac function was assessed with Langendorff perfusion and echocardiography. Under basal conditions, ABC-me(+/-) mice had normal heart structure, hemodynamic function, mitochondrial respiration, and oxidative status. However, after ischemia/reperfusion, the recovery of hemodynamic function was reduced by 50% in ABC-me(+/-) hearts as a result of impairments in both systolic and diastolic function. This reduction was associated with impaired mitochondrial bioenergetic function and with oxidative damage to both mitochondrial lipids and sarcoplasmic reticulum calcium ATPase after reperfusion. Treatment of ABC-me(+/-) hearts with the superoxide dismutase/catalase mimetic EUK-207 prevented oxidative damage to mitochondria and sarcoplasmic reticulum calcium ATPase and restored mitochondrial and cardiac function to wild-type levels after reperfusion.
  
  
  CONCLUSIONS
  Inactivation of 1 allele of ABC-me increases the susceptibility to oxidative stress induced by ischemia/reperfusion, leading to increased oxidative damage to mitochondria and sarcoplasmic reticulum calcium ATPase and to impaired functional recovery. Thus, ABC-me is a novel gene that determines the ability to tolerate cardiac ischemia/reperfusion.
authors.affiliation: Department of Medicine, Obesity and Diabetes Research Centers, Boston University School of Medicine, 650 Albany St, Room 804, Boston, MA 02118, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Liesa
authors.forename: Ivan
authors.initials: I
authors.lastname: Luptak
authors.forename: Fuzhong
authors.initials: F
authors.lastname: Qin
authors.forename: Brigham B
authors.initials: BB
authors.lastname: Hyde
authors.forename: Ergun
authors.initials: E
authors.lastname: Sahin
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Siwik
authors.forename: Zhengkun
authors.initials: Z
authors.lastname: Zhu
authors.forename: David R
authors.initials: DR
authors.lastname: Pimentel
authors.forename: X Julia
authors.initials: XJ
authors.lastname: Xu
authors.forename: Neil B
authors.initials: NB
authors.lastname: Ruderman
authors.forename: Karl D
authors.initials: KD
authors.lastname: Huffman
authors.forename: Susan R
authors.initials: SR
authors.lastname: Doctrow
authors.forename: Lauren
authors.initials: L
authors.lastname: Richey
authors.forename: Wilson S
authors.initials: WS
authors.lastname: Colucci
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002306:Cardiac Volume / Q000502:physiology; D002374:Catalase / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D016254:Mutagenesis, Insertional; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D009942:Organometallic Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D020127:Recovery of Function / Q000235:genetics*; D013482:Superoxide Dismutase / Q000378:metabolism; D017725:Ventricular Pressure / Q000502:physiology
chemical_list: D018528:ATP-Binding Cassette Transporters; C498824:Abca2 protein, mouse; C476761:EUK 207; D009942:Organometallic Compounds; D002374:Catalase; D013482:Superoxide Dismutase