Abstract 15685: Copper Transport Protein Antioxidant-1 Mediates Vascular Remodeling via Promoting Macrophage Infiltration and Copper- and Rac1-dependent Vascular Migration
Vascular smooth muscle cell (VSMC) migration and inflammation are critically important in neointimal formation following vascular injury and atherosclerosis lesion formation. Copper (Cu) chelator inhibits neointimal formation with unknown mechanism. We previously demonstrated that Cu chaperone antioxidant-1 (Atox1) is involved in Cu-induced cell growth and that Cu transporter ATP7A, which obtains Cu from Atox1, is involved in VSMC migration. However, the role of Atox1 in neointimal formation after injury is unknown. In vivo, Atox1 is ubiquitously expressed in VSMCs and endothelial cells of noninjured vessels in wild type (WT) mice. Following wire injury, Atox1 expression is upregulated in injured vessels, and its expression is colocalized with ATP7A (+) cells, mainly in CD45 (+) inflammatory cells at day 3 and 7, and in neointimal α-smooth muscle actin (α-SMA) (+) VSMCs at day 14. Atox1 KO mice show significant inhibition of neointimal formation (I/M ratio: 53%) and fibrosis (34%) at day 21 compared to WT mice, which is associated with decreased α-SMA (+) cells infiltration within neointima at day 14. Mechanistically, in cultured VSMC, siRNAs for Atox1 or ATP7A inhibit VSMC migration induced by platelet-derived growth factor (PDGF) (77% and 70%) or wound scratch (63% and 60%). PDGF promotes Atox1 binding to ATP7A within 5 min via Cu-dependent manner, which in turn recruits Rac1 to the Atox1/ATP7A complex. Functional significance of this complex is demonstrated that Atox1 siRNA inhibits PDGF-induced ATP7A and Rac1 translocation to the leading edge, thereby inhibiting Cu- and Rac1-dependent lamellipodia formation. Furthermore, Atox1 KO mice show decreased perivascular macrophage infiltration at day 7 and 14 (56% and 57%). This result is further confirmed that thioglycollate-induced peritoneal macrophage recruitment is reduced in Atox1 KO mice (62%), suggesting that Atox1 also mediates macrophage recruitment in inflammatory conditions. In summary, Atox1 is involved in neointimal formation after vascular injury, through promoting VSMC migration and inflammation in injured vessels. Our results will provide new insight into Atox1 as a potential therapeutic target for the crucial events in inflammation and VSMC migration-related vascular diseases.
- © 2012 by American Heart Association, Inc.