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(Circulation Research. 2008;103:598.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Peroxiredoxin1 Prevents Excessive Endothelial Activation and Early Atherosclerosis

Janka Kisucka^*, Anil K. Chauhan^*, Ian S. Patten, Ayce Yesilaltay, Carola Neumann, Richard A. Van Etten, Monty Krieger, Denisa D. Wagner

From Immune Disease Institute Inc (J.K., A.K.C., I.S.P., D.D.W.) and the Department of Pathology (J.K., A.K.C., D.D.W.), Harvard Medical School, Boston, Mass; Department of Biology (A.Y., M.K.), Massachusetts Institute of Technology, Cambridge, Mass; Medical University of South Carolina (C.N.), Cell and Molecular Pharmacology, Charleston; and Molecular Oncology Research Institute (R.A.V.E.), Tufts–New England Medical Center, Boston, Mass.

Correspondence to Denisa D. Wagner, Immune Disease Institute and Department of Pathology, Harvard Medical School, 800 Huntington Ave, Boston, MA 02115. E-mail wagner{at}idi.harvard.edu

The peroxiredoxin (Prdx) family of antioxidant enzymes uses redox-active cysteines to reduce peroxides, lipid hydroperoxides, and peroxynitrites. Prdx1 is known to be important to protect red blood cells against reactive oxygen species and in tumor prevention. In this study, the role of Prdx1 in inflammation, thrombosis, and atherosclerosis was investigated. Using intravital microscopy, we showed that the number of leukocytes rolling per minute in unstimulated veins was increased by 2.5-fold in Prdx1^–/– compared to Prdx1^+/+ mice. In Prdx1^–/– mice, 50% of leukocytes rolled at a velocity <10 µm/sec compared with 10% in Prdx1^+/+ mice, suggesting that adhesion molecule density on the endothelium may have been increased by Prdx1 deficiency. Indeed, endothelial P-selectin, soluble P-selectin, and von Willebrand factor in plasma were increased in Prdx1^–/– mice compared to Prdx1^+/+ mice, indicating elevated Weibel–Palade body release. In contrast to this excessive endothelial activation, Prdx1^–/– platelets showed no sign of hyperreactivity, and their aggregation both in vitro and in vivo was normal. We also examined the role of Prdx1 in the apoE^–/– murine spontaneous model of atherosclerosis. Prdx1^–/–/apoE^–/– mice fed normal chow developed larger, more macrophage-rich aortic sinus lesions than Prdx1^+/+/apoE^–/– mice, despite similar amounts and size distributions of cholesterol in their plasma lipoproteins. Thus, Prdx1 protects against excessive endothelial activation and atherosclerosis, and the Prdx1^–/– mice could serve as an animal model susceptible to chronic inflammation.

Key Words: inflammation • atherosclerosis • antioxidant enzymes • endothelium • peroxiredoxin

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