PDGF signaling: Peroxidase induces a change of heart

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Mammalian peroxidase PrxII regulates platelet-derived growth factor (PDGF) signaling during vascular remodelling in cardiovascular disease.

The mitogen platelet-derived growth factor (PDGF) regulates cell growth, proliferation and migration by initiating signaling through protein tyrosine phosphorylation. One of the consequences of PDGF signaling is the production of H₂O₂. Choi et al. now report that the mammalian peroxidase PrxII, which eliminates H₂O₂ in response to growth factor signaling, is a negative regulator of PDGF receptor (PDGFR) function during vascular remodelling.

The authors observed that total PDGF-induced protein tyrosine phosphorylation was higher in mouse embryonic fibroblasts (MEFs) lacking PrxII (PrxII^-/-) compared with wild type cells, and coincided with an increase in H₂O₂ production. In rescue experiments with retrovirally expressed PrxII, these effects were abolished and a reduction in PDGF-induced proliferation and PDGF-mediated adhesion and chemotactic migration was observed.

PrxII null MEFs exhibited an increase in the phosphorylation of key tyrosine residues in both PDGFR and the downstream signaling molecule phospholipase C gamma 1 (PLC- gamma 1). Moreover, in PrxII^-/-MEFs there was a higher kinase activity of PDGFR towards PLC gamma 1. Co-immunoprecipitation and immunostaining experiments revealed that upon ligand stimulation active PrxII is recruited to PDGFR. Since PrxII can suppress PDGFR phosphorylation in response to exogenous H₂O₂ and appears to scavenge diffuse H₂O₂, PrxII’s role might be to restrict the action of H₂O₂close to the receptor. A possible mechanism is that the peroxidase allows oxidatively inactivated protein tyrosine phosphatases to be reactivated by removing endogenous H₂O₂.

PDGF is known to regulate smooth muscle cell proliferation and migration during vascular remodelling. Indeed, PrxII overexpression suppressed tyrosine phosphorylation of PDGFR and PLC- gamma 1, as well as reducing PDGF-induced chemotactic migration of vascular smooth muscle cells (VSMCs).

To examine the physiological role of the peroxidase, the authors compared injured carotid arteries of PrxII^-/- mice with those of wild type mice. Neointimal layers were thicker in PrxII^-/- mice — an effect abolished by administration of an anti-PDGF antibody — and PDGFR phosphorylation was higher in the injured arteries when compared with wild type. These results suggest that PrxII influences the PDGF-dependent proliferation and migration of smooth muscle cells during vascular remodelling.

Thus, Choi et al. have uncovered a new role for PrxII in the regulation of PDGF signaling, which appears to be directly linked to its biological function during cardiovascular injury.

Myrto Raftopoulou
Signaling Gateway

References

Choi, Min Hee, Lee, In Kyung, Kim, Gyung Whan, Kim, Bang Ul, Han, Ying-Hao , Yu, Dae-Yeul , Park, Hye Sun, Kim, Kyung Yong, Lee, Jong Seo, Choi, Chulhee, Bae, Yun Soo, Lee, Byung In, Rhee, Sue Goo, & Kang, Sang Won. Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II. Nature 435, 347–353 (19 May 2005); nature03587 | Article |