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Targeted disruption of peroxiredoxin 6 gene renders the heart vulnerable to ischemia-reperfusion injury

Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, Connecticut; and Institute for Environmental Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

Submitted 18 April 2006 ; accepted in final form 18 May 2006

Peroxiredoxin 6 (Prdx6) is a novel peroxidase enzyme belonging to the Prdx family, which in mammals contains five more peroxiredoxins (Prdx1–Prdx5). Like glutathione peroxidase (GSHPx) and catalase, Prdx6 possesses H₂O₂-scavenging activities, and, like the former, it also removes hydroperoxides. Since significant amounts of catalase and GSHPx are present in the heart contributing toward the attenuation of H₂O₂ and hydroperoxides formed during ischemia-reperfusion injury and thereby providing cardioprotection, we asked whether Prdx6 also has any role in this process. In the present study we used Prdx6^–/– mice to assess the role of Prdx6 in ischemic injury. Western blot analysis revealed the absence of any Prdx activity in the Prdx6^–/– mouse heart, while the GSHPx-1 and catalase levels remained unchanged. Randomly selected hearts from Prdx6^–/– mice and wild-type mice were subjected to 30 min of global ischemia followed by 120 min of reperfusion at normothermia. The hearts from the Prdx6^–/– mice were more susceptible to ischemic reperfusion injury as evidenced by reduced recovery of left ventricular function, increased myocardial infarct size, and higher amount of apoptotic cardiomyocytes compared with wild-type mouse hearts. These Prdx6^–/– hearts were also subjected to a higher amount of oxidative stress as evidenced by the presence of higher amount of malondialdehyde. The present study thus indicates a nonredundant role of Prdx6 in myocardial ischemic reperfusion injury as catalase, and GSHPx could not make up for the deficiency of Prdx6 activities.

redox signaling; reactive oxygen species; glutathione; catalase; glutathione peroxidase; peroxiredoxin gene knockout mice

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