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2-Methoxyestradiol blocks the RhoA/ROCK1 pathway in human aortic smooth muscle cells.
Journal article

2-Methoxyestradiol blocks the RhoA/ROCK1 pathway in human aortic smooth muscle cells.

  • Rigassi L Department of Reproductive Endocrinology, University Hospital Zurich, Zurich, Switzerland;
  • Barchiesi Bozzolo F Department of Reproductive Endocrinology, University Hospital Zurich, Zurich, Switzerland;
  • Lucchinetti E Department of Anesthesiology and Pain Medicine and Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada; and.
  • Zaugg M Department of Anesthesiology and Pain Medicine and Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada; and.
  • Fingerle J Preclinical Pharma Research 60/209, F Hoffmann-La-Roche, Basel, Switzerland.
  • Rosselli M Department of Reproductive Endocrinology, University Hospital Zurich, Zurich, Switzerland;
  • Imthurn B Department of Reproductive Endocrinology, University Hospital Zurich, Zurich, Switzerland;
  • Jackson EK Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
  • Dubey RK Department of Reproductive Endocrinology, University Hospital Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; raghvendra.dubey@usz.ch.
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  • 2015-10-22
Published in:
  • American journal of physiology. Endocrinology and metabolism. - 2015
2-methoxyestradiol
ROCK1
RhoA
cytokinesis
myosin light chain
myosin phosphatase targeting subunit
2-Methoxyestradiol
Aorta
Cells, Cultured
Cytokinesis
Dose-Response Relationship, Drug
Down-Regulation
Estradiol
Female
Humans
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Signal Transduction
rho-Associated Kinases
rhoA GTP-Binding Protein
English 2-Methoxyestradiol (2-ME), a metabolite of estradiol with little affinity for estrogen receptors, inhibits proliferation of vascular smooth muscle cells; however, the molecular mechanisms underlying this effect are incompletely understood. Our previous work shows that 2-ME inhibits initiation (blocks phosphorylation of ERK and Akt) and progression (reduces cyclin expression and increases expression of cyclin inhibitors) of the mitogenic pathway and interferes with mitosis (disrupts tubulin organization). Because the RhoA/ROCK1 pathway (RhoA → ROCK1 → myosin phosphatase targeting subunit → myosin light chain) is involved in cytokinesis, herein we tested the concept that 2-ME also blocks the RhoA/ROCK1 pathway. Because of the potential importance of 2-ME for preventing/treating vascular diseases, experiments were conducted in female human aortic vascular smooth muscle cells. Microarray transcriptional profiling suggested an effect of 2-ME on the RhoA/ROCK1 pathway. Indeed, 2-ME blocked mitogen-induced GTP-bound RhoABC expression and membrane-bound RhoA, suggesting interference with the activation of RhoA. 2-ME also reduced ROCK1 expression, suggesting reduced production of the primary downstream signaling kinase of the RhoA pathway. Moreover, 2-ME inhibited RhoA/ROCK1 pathway downstream signaling, including phosphorylated myosin phosphatase targeting subunit and myosin light chain; the ROCK1 inhibitor H-1152 mimicked these effects of 2-ME; both 2-ME and H-1152 blocked cytokinesis. 2-ME also reduced the expression of tissue factor, yet another downstream signaling component of the RhoA/ROCK1 pathway. We conclude that 2-ME inhibits the pathway RhoA → ROCK1 → myosin phosphatase targeting subunit → myosin light chain, and this likely contributes to the reduced cytokinesis in 2-ME treated HASMCs.
Language
  • English
Open access status
green
Identifiers
Persistent URL
https://sonar.ch/global/documents/160133
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