Abstract 12585: PKC-MMP-14 Axis Regulates Endothelial Soluble Tie-2 (sTie-2) Production: Involvement of sTie-2 in Diabetes Mellitus-Associated Vascular Complications
Endothelial Tie-2 signal is critical in vessel maturation/stabilization. In contrast, it is known that endothelial Tie-2 is converted to soluble Tie-2 (sTie-2). The pathophysiological role of soluble conversion, however, remains unclear. We here investigated the detail molecular mechanisms for conversion of Tie-2 to sTie-2, and the significance of sTie-2 in diabetes mellitus (DM)-associated vascular complications. STie-2 was detected in human plasma, which consisted mainly of two different extracellular fragments of Tie-2, approximate 75kDa (short form sTie-2/S-sTie-2) and 115kDa (long form sTie-2/L-sTie-2). The soluble forms were also produced in human endothelial cells (ECs) in vitro. S-sTie-2 production but not L-sTie-2 was significantly reduced with treatment of MMP-14 siRNA in ECs. PMA specifically enhanced S-sTie-2 production, resulting in the reduced level of endothelial full length Tie-2 expression. PMA-enhanced production of S-sTie-2 and reduction of endothelial Tie-2 level were significantly blocked with treatment of a PKC broad inhibitor or MMP-14 siRNA. In contrast, PMA up-regulated MMP-14 expression in ECs, and the effect of PMA was completely inhibited with treatment of the PKC inhibitor. These findings suggested that endothelial Tie-2 level was post-translationally regulated by PKC-MMP-14 axis-dependent sTie-2 production in ECs. On the basis of these evidences, we evaluated concentration of sTie-2 in vitreous humor from patients with or without diabetic retinopathy, because metabolic disorder-associated chronic PKC activation is one of causes of DM-associated vascular complication. As a result, sTie-2 concentration was significantly higher in vitreous humor from DM-patients with both diabetic macular edema (n = 20) or with proliferative diabetic retinopathy (n = 11) compared to that from non-DM patients (n = 24). Together, PKC-MMP-14 axis may lead to dysfunction of Ang-1/Tie-2 system and play an important role in DM-associated vascular complications.
- © 2011 by American Heart Association, Inc.