Molecular Cardiology Mitochondrial Transporter ATP Binding Cassette Mitochondrial Erythroid Is a Novel Gene Required for Cardiac Recovery After Ischemia/Reperfusion

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. Methods and Results—Mice harboring 1 functional allele of ABC-me (ABC-me ϩ/Ϫ) 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 ϩ/Ϫ 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 ϩ/Ϫ 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 ϩ/Ϫ hearts with the superoxide dismutase/catalase mimetic EUK-207 prevented oxidative damage to mitochondria and sarcoplas-mic 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. A cute coronary occlusion leading to cardiac ischemia/reper-fusion is a major cause of mortality in Western societies. Multiple lines of evidence demonstrate that increased oxidative stress and mitochondrial dysfunction are key mediators of the cardiac dysfunction induced by ischemia/reperfusion. 1–15 After ischemia/reperfusion, oxidative stress may impair mitochondrial electron transport, 2,4,8 –10 leading to decreased mitochondrial ATP synthesis and respiration and thereby contributing to diastolic stiffness and contractile dysfunction. 8 –10,16 Conversely, the sudden increase in mitochondrial respiration during early reperfusion and the impairment in electron transport chain activity may increase the production of reactive oxygen species and contribute to oxidative damage. 4,5,8,12,17 Furthermore, the opening of the mitochondrial transition pore and mitochon-drial fission promote cardiac myocyte death after ischemia/reperfusion. The central role that oxidative stress plays in myocardial recovery from ischemia/reperfusion has been well illustrated. Targeting antioxidants to mitochondria or overexpression …