Transgelin 2 Participates in Lovastatin-Induced Anti-Angiogenic Effects in Endothelial Cells through a Phosphorylated Myosin Light Chain-Related Mechanism

BACKGROUND: Anti-angiogenic activity is considered to play a key role in the statin-induced anti-tumor effects. We aimed to identify new targets underlying this pleiotropic effect of lovastatin. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the inhibitory effects of lovastatin on endothelial cell biology and angiogenesis in vitro. Lovastatin at high doses inhibited endothelial cell migration and tube formation. Using two-dimensional gel electrophoresis followed by mass spectrometry, we identified the up-regulation of the actin-binding protein transgelin 2 in endothelial cells following treatment with lovastatin. Changes in transgelin 2 levels were confirmed by Western blot and confocal microscopy. We further demonstrated that the Rho signaling inactivation and actin depolymerization contributed to the up-regulation of transgelin 2. The knockdown of transgelin 2 by siRNA dramatically enhanced endothelial migration and tube formation, and meanwhile attenuated the inhibitory effects of lovastatin on cell motility. Moreover, the lovastatin-induced inhibition of myosin light chain phosphorylation was also reversed by transgelin 2 knockdown. The activation of Rho GTPase in the absence of transgelin 2 may represent a mechanism underlying the regulation of phosphorylated myosin light chain by transgelin 2. CONCLUSIONS/SIGNIFICANCE: These results strongly imply a novel role for transgelin 2 in the angiostatic activities of lovastatin.