Pim Protein Kinase-3 Is Regulated by TNF-α and Promotes Endothelial Cell Sprouting

Tumor necrosis factor-alpha (TNF-alpha) plays an important role in pathological angiogenesis associated with inflammatory response. Pim-3 kinase belonging to serine/threonine protein kinases is a potent suppressor of myc-induced apoptosis. We have recently demonstrated that Pim-3 plays an essential role in endothelial cell (EC) spreading and migration. In this study, we showed that TNF-alpha transiently increased Pim-3 mRNA expression, and this was mediated through Tumor necrosis factor-alpha receptor-1 (TNFR1) pathway in ECs. TNF-alpha could promote stabilization of Pim-3 mRNA in ECs. Small-interfering RNA (siRNA)-mediated gene knockdown of Pim-3 significantly impaired TNF-alpha-induced formation of EC membrane protrusions in vitro. Furthermore, Pim-3 silencing inhibited EC sprouting in subcutaneous Matrigel in vivo. eNOS mRNA abundance was lower in Pim-3 siRNA transfected ECs compared with the control ECs. These observations suggest that Pim-3 plays a role in TNF-alpha-induced angiogenesis.