Vascular Injury Involves the Overoxidation of Peroxiredoxin Type II and is Recovered by the Peroxiredoxin-Activity Mimetic that Induces Reendothelialization
Background—Typical 2-Cys peroxiredoxin (Prx) is inactivated by overoxidation of the peroxidatic cysteine residue under oxidative stress. However, the significance in the context of vascular disease is unknown.
Methods and Results—The immunohistochemical analyses revealed that 2-Cys Prxs, particularly Prx type II, are heavily overoxidized in balloon-injured rodent carotid vessels and in human atherosclerotic lesions. Consistent with this observation, the selective depletion of Prx II exacerbated neointimal hyperplasia in injured carotid vessels. We also found that the epipolythiodioxopiperazine (ETP) class of fungal metabolites exhibited an enzyme-like activity mimicking 2-Cys Prx peroxidase and manifestly eliminated the intracellular H2O2 in the vascular cells. Functionally, the ETPs reciprocally regulated the PDGFRβ- and VEGFR2-mediated signaling in these vascular cells by replacing Prx II. As a consequence, the ETPs inhibited proliferative and migratory activities of smooth muscle cells, while they promoted those of endothelial cells in vitro. Moreover, administration of the ETPs to the injured carotid vessels resulted in a successful recovery by inhibiting neointimal hyperplasia without causing cytotoxicity and simultaneously inducing reendothelialzation.
Conclusions—This study reveals for the first time the involvement of the 2-Cys Prx overoxidation and hereafter the therapeutic use of their activity mimetic in vascular injuries like stenting.
- Tyrosine kinase receptor
- reactive oxygen species
- signal transduction
- Received January 30, 2013.
- Revision received June 14, 2013.
- Accepted June 24, 2013.