Targeted disruption of the mouse Sod I gene makes the hearts vulnerable to ischemic reperfusion injury.
The role of Cu/Zn-superoxide dismutase (SOD) in myocardial ischemic reperfusion injury was studied by using a mouse model with targeted disruption of the mouse Sod I gene. Inactivation of the functional mouse Sod I gene in hearts by gene targeting (Sod I(+/-)) resulted in a 50% reduction of Cu/Zn-SOD mRNA and significant reduction of Cu/Zn-SOD enzyme activity compared with that of wild-type Sod I(+/+) mice. Cu/Zn-SOD mRNA could not be detected in Sod I(-/-) heart. The isolated buffer-perfused hearts from the knockout mice devoid of any functional copy of the Sod I (Sod I(-/-)) and matched nontransgenic control mice were subjected to 30 minutes of global ischemia followed by 2 hours of reperfusion. For both groups of mice, the postischemic functional recovery for the hearts was lower than the baseline, but the recovery for the Sod I(-/-) was less compared with the wild-type mice. Thus, the postischemic recovery of the developed force and the maximum first derivative of the developed force were consistently lower for the Sod I(-/-) mouse hearts compared with wild-type control hearts. The coronary flow was lower compared with the baseline levels for both groups of hearts, but there was no significant difference between the groups. The myocardial infarction determined from the ratio of infarct size/area of risk was higher for the Sod I(-/-) mice compared with the control mice. The amount of creatine kinase release from the wild-type mouse hearts was less compared with the Sod I(-/-) mouse hearts. In concert, a reduced amount of oxidative stress was found in the hearts of wild-type mice compared with Sod I(-/-) mouse hearts. These results documented that Sod I(-/-) mouse hearts were more susceptible to ischemic reperfusion injury compared with corresponding wild-type mouse hearts, suggesting that the Sod I gene constitutes an important defense element for the hearts.
Yoshida
T
T
Cardiovascular Research Center, Department of Surgery, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA.
Maulik
N
N
Engelman
R M
RM
Ho
Y S
YS
Das
D K
DK
D000818:Animals; D003402:Creatine Kinase / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006321:Heart / Q000503:physiopathology; D017665:Hydroxyl Radical / Q000378:metabolism; D066298:In Vitro Techniques; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009203:Myocardial Infarction / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology*; D000072105:Superoxide Dismutase-1
D017665:Hydroxyl Radical; D008315:Malondialdehyde; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003402:Creatine Kinase