Peroxiredoxin 2 deficiency exacerbates atherosclerosis in apolipoprotein E-deficient mice.

Abstract

RATIONALE:

Peroxiredoxin 2 (Prdx2), a thiol-specific peroxidase, has been reported to regulate proinflammatory responses, vascular remodeling, and global oxidative stress.

OBJECTIVE:

Although Prdx2 has been proposed to retard atherosclerosis development, no direct evidence and mechanisms have been reported.

METHODS AND RESULTS:

We show that Prdx2 is highly expressed in endothelial and immune cells in atherosclerotic lesions and blocked the increase of endogenous H(2)O(2) by atherogenic stimulation. Deficiency of Prdx2 in apolipoprotein E-deficient (ApoE(-/-)) mice accelerated plaque formation with enhanced activation of p65, c-Jun, JNKs, and p38 mitogen-activated protein kinase; and these proatherogenic effects of Prdx2 deficiency were rescued by administration of the antioxidant ebselen. In bone marrow transplantation experiments, we found that Prdx2 has a major role in inhibiting atherogenic responses in both vascular and immune cells. Prdx2 deficiency resulted in increased expression of vascular adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemotactic protein-1, which led to increased immune cell adhesion and infiltration into the aortic intima. Compared with deficiency of glutathione peroxidase 1 or catalase, Prdx2 deficiency showed a severe predisposition to develop atherosclerosis.

CONCLUSIONS:

Prdx2 is a specific peroxidase that inhibits atherogenic responses in vascular and inflammatory cells, and specific activation of Prdx2 may be an effective means of antiatherogenic therapy.

• Authors: Jong-Gil Park, Ji-Young Yoo, Se-Jin Jeong, Jae-Hoon Choi, Mi-Ran Lee, Mi-Ni Lee, Jeong Hwa Lee, Hyoung Chin Kim, Hanjoong Jo, Dae-Yeul Yu, Sang Won Kang, Sue Goo Rhee, Mun-Han Lee, Goo Taeg Oh
• Journal: Circulation research (Circ Res) Vol. 109 Issue 7 Pg. 739-49 (Sep 16 2011) ISSN: 1524-4571 [Electronic] United States
• PMID: 21835911 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Apolipoproteins E
• Azoles
• Ccl2 protein, mouse
• Chemokine CCL2
• Isoindoles
• Organoselenium Compounds
• Rela protein, mouse
• Transcription Factor RelA
• Vascular Cell Adhesion Molecule-1
• Intercellular Adhesion Molecule-1
• ebselen
• Hydrogen Peroxide
• Peroxiredoxins
• Catalase
• Glutathione Peroxidase
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Glutathione Peroxidase GPX1
• Gpx1 protein, mouse

Topics

• Animals
• Antioxidants (pharmacology)
• Aorta (drug effects, enzymology, immunology, pathology)
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (enzymology, genetics, immunology, pathology, prevention & control)
• Azoles (pharmacology)
• Bone Marrow Cells (enzymology)
• Bone Marrow Transplantation
• Catalase (genetics, metabolism)
• Chemokine CCL2 (metabolism)
• Disease Models, Animal
• Endothelial Cells (enzymology)
• Glutathione Peroxidase (deficiency, genetics)
• Hydrogen Peroxide (metabolism)
• Intercellular Adhesion Molecule-1 (metabolism)
• Isoindoles
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Organoselenium Compounds (pharmacology)
• Peroxiredoxins (deficiency, genetics)
• Severity of Illness Index
• Signal Transduction
• Time Factors
• Transcription Factor RelA (metabolism)
• Vascular Cell Adhesion Molecule-1 (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)
• Glutathione Peroxidase GPX1