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.


RESULTS
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
These results strongly imply a novel role for transgelin 2 in the angiostatic activities of lovastatin.
State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences and Institute of System Biomedicine, Peking University, Beijing, China.
Yuan
Y
Xiao
Yuhua
Y
Li
Jing
J
Han
Yan
Y
Pan
Lu
L
Tie
Xuejun
X
Li
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology*; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D018613:Microscopy, Confocal; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D018994:Myosin Light Chains / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering
D020533:Angiogenesis Inhibitors; D008840:Microfilament Proteins; D009124:Muscle Proteins; D018994:Myosin Light Chains; D034741:RNA, Small Interfering; C051615:transgelin; D008148:Lovastatin