Abstract 15693: Novel Role of Copper Transport Proteins in Insulin-Induced Signaling Linked to Extracellular SOD Activity and Vascular Proliferation
Insulin has both vasoprotective and hyperproliferative functions in the vasculature in diabetes mellitus (DM); however, how insulin induces opposite effects remains unknown. We have demonstrated that copper (Cu) plays an important role in cell proliferation and activating Cu-containing antioxidant enzymes such as extracellular SOD (ecSOD) which preserves NO bioavailability. Intracellular Cu levels are tightly controlled by the Cu transport proteins including Cu chaperone antioxidant 1 (Atox1) and Cu exporter ATP7A which obtains Cu from Atox1 and transfer Cu to ecSOD. We thus hypothesize that Cu transport proteins may play a role in insulin-induced vascular function. Here we show that low concentration of insulin (10 nM) increases ecSOD activity (50%) and increased ATP7A protein expression in isolated DM aorta. This in turn increases endothelial NO bioactivity via promoting acetylcholine-induced vasorelaxation (P<0.05) of resistant mesenteric arties. These insulin-induced Akt-ATP7A-ecSOD-mediated vasoprotective effects are impaired in vessels of type1 DM with hypoinsulinemia, and rescued by insulin addition. Mechanistically, in cultured vascular smooth muscle cells (VSMCs), the effect of insulin on ATP7A function are inhibited by Akt inhibitor, Akt1/2/3i, Cu chelator TM, but not by ERK inhibitor, PD98059, or Atox1 siRNA. By contrast, high concentration of insulin (100 nM) significantly increases proliferation (P<0.001) and cyclin D1 expression (2-fold) in VSMCs, which are blocked by Atox1 siRNA, Cu chelator TM, or ERK inhibitor, but not by ATP7A siRNA or Akt inhibitor. In addition, Atox1 siRNA, but not ATP7A siRNA, significantly inhibits insulin (100 nM)-induced pERK without affecting p-Akt. These results suggest that the Atox1-Erk axis is involved in hyperinsulinemia-induced VSMC proliferation. In summary, low concentration of insulin promotes endothelial function via the Akt-ATP7A-ecSOD pathway, whereas high concentration of insulin increases VSMC proliferation via the Atox1-Erk signaling pathway. Thus, Cu transport proteins are important therapeutic targets in normal physiological and pathological insulin signaling in vascular tissue.
- © 2012 by American Heart Association, Inc.