2-methoxyestradiol inhibits atorvastatin-induced rounding of human vascular smooth muscle cells
Article first published online: 23 NOV 2009
Copyright © 2009 Wiley-Liss, Inc.
Journal of Cellular Physiology
Volume 222, Issue 3, pages 556–564, March 2010
How to Cite
Yin, H., Gui, Y. and Zheng, X.-L. (2010), 2-methoxyestradiol inhibits atorvastatin-induced rounding of human vascular smooth muscle cells. J. Cell. Physiol., 222: 556–564. doi: 10.1002/jcp.21970
- Issue published online: 24 DEC 2009
- Article first published online: 23 NOV 2009
- Manuscript Accepted: 22 SEP 2009
- Manuscript Received: 27 JUL 2009
- Canadian Institutes of Health Research and Pfizer Canada Inc.. Grant Number: 60-28050-RT732591 60-28050-RT732688
The cardiovascular benefits of statins, including atorvastatin (ATV), have been reported to be gender-dependent, but the underlying mechanism is unclear. In this study we examine whether estrogen and its metabolite, 2-methoxyestradiol (2ME), affect the rounding response of human vascular smooth muscle cells (SMCs) induced by ATV. Twenty-four hour treatment with ATV (10–100 µM) induced rounding of cultured human SMCs. Addition of 2ME (1–20 µM), but not 17β-estradiol, for 2 h induced re-spreading of rounded cells. Our further studies showed that the effects of 2ME were mimicked by microtubule-disrupting drugs and inhibited by taxol. Inhibition of RhoA and ROCK (Rho-kinase) by C3-toxin and H-1152, respectively, blocked 2ME effects. 2ME effects were also blocked by treatment with either actin-interfering drugs, such as cytochalasin D and jasplakinolide, or myosin inhibitor blebbistatin. ML-7 and -9, the inhibitors for myosin light chain kinase, inhibited 2ME effect as well. ATV treatment induced a decrease of F-actin content and Thr18/Ser19 dual phosphorylation of myosin regulatory light chain (MRLC), which was rescued by 2ME or mevalonate. The rescue effects of 2ME on F-actin content and MRLC dual phosphorylation were abolished by taxol or H-1152. In addition, kinesin Eg5 inhibitor monastrol and dynein inhibitor erythro-9-3-(2-hydroxynonyl) adenine (EHNA) significantly blocked 2ME effects. Finally, our results revealed that 2ME inhibited the migration of SMCs induced by ATV (0.1 µM) in wound healing assay and Boyden chamber assay. In summary, our data show that 2ME, but not estrogen, inhibits ATV-induced rounding of human SMCs through induction of microtubule disassembly and activation of the Rho-ROCK-actinomyosin pathway. J. Cell. Physiol. 222: 556–564, 2010. © 2009 Wiley-Liss, Inc.