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Vascular injury involves the overoxidation of peroxiredoxin type II and is recovered by the peroxiredoxin activity mimetic that induces reendothelialization.

ABSTRACT: 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.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 class of fungal metabolites exhibited an enzyme-like activity mimicking 2-Cys Prx peroxidase and manifestly eliminated the intracellular H?O? in the vascular cells. Functionally, the epipolythiodioxopiperazines reciprocally regulated the platelet-derived growth factor receptor-?- and vascular endothelial growth factor receptor-mediated signaling in these vascular cells by replacing Prx II. As a consequence, the epipolythiodioxopiperazines inhibited the proliferative and migratory activities of smooth muscle cells but promoted those of endothelial cells in vitro. Moreover, administration of the epipolythiodioxopiperazines to the injured carotid vessels resulted in a successful recovery by inhibiting neointimal hyperplasia without causing cytotoxicity and simultaneously inducing reendothelialization.This study reveals for the first time the involvement of the 2-Cys Prx overoxidation and thus the therapeutic use of their activity mimetic in vascular injuries like stenting.

SUBMITTER: Kang DH

PROVIDER: S-EPMC5479486 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Vascular injury involves the overoxidation of peroxiredoxin type II and is recovered by the peroxiredoxin activity mimetic that induces reendothelialization.

Kang Dong Hoon DH Lee Doo Jae DJ Kim Jiran J Lee Joo Young JY Kim Hyun-Woo HW Kwon Kihwan K Taylor W Robert WR Jo Hanjoong H Kang Sang Won SW

Circulation 20130702 8

<h4>Background</h4>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.<h4>Methods and results</h4>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 e ...[more]

PMID: 23820076

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Project description:BackgroundIntimal injury rapidly activates TGFβ and enhances vascular repair by the growth of endothelial (EC) and vascular smooth muscle cells (VSMC). The response to the TGFβ family of growth factors can be modified by BAMBI (BMP, Activin, Membrane Bound Inhibitor) acting as a non-signaling, competitive antagonist of TGFβ type I receptors such as ALK 1 and 5. In vivo the effect of BAMBI will depend on its cell-specific expression and of that of the ALK type receptors. We recently reported EC restricted BAMBI expression and genetic elimination of BAMBI resulting in an in vitro and in vivo phenotype characterized by endothelial activation and proliferation involving alternative pathway activation by TGFβ through ALK 1.Methodology/principal findingsTo test the hypothesis that BAMBI modulates arterial response to injury via its effects on endothelial repair and arterial wall neovascularization we used a model of femoral arterial denudation injury in wild type (WT) and BAMBI(-/-) mice. Arterial response was evaluated at 2 and 4 weeks after luminal endothelial denudation of femoral arteries. The BAMBI(-/-) genotype mice showed accelerated luminal endothelial repair at 2 weeks and a highly unusual increase in arterial wall neovascularization compared to WT mice. The exuberant intimal and medial neovessel formation with BAMBI(-/-) genotype was also associated with significant red blood cell extravasation. The bleeding into the neointima at 2 weeks transiently increased it's area in the BAMBI(-/-)genotype despite the faster luminal endothelial repair in this group. Vascular smooth muscle cells were decreased at 2 weeks in BAMBI(-/-) mice, but comparable to wild type at 4 weeks.Conclusions/significanceThe absence of BAMBI results in a highly unusual surge in arterial wall neovascularization that surprisingly mimiks features of intra-plaque hemorrhage of advanced atheroma in a mechanical injury model. This suggests important effects of BAMBI on arterial EC homeostasis that need to be further studied in a model of inflammatory atherosclerosis.

Dataset Information

Vascular injury involves the overoxidation of peroxiredoxin type II and is recovered by the peroxiredoxin activity mimetic that induces reendothelialization.

Publications

Vascular injury involves the overoxidation of peroxiredoxin type II and is recovered by the peroxiredoxin activity mimetic that induces reendothelialization.

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