Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 19, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm017
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Shear stress-induced activation of the AMP-activated protein kinase regulates FoxO1a and angiopoietin-2 in endothelial cells
Vascular Signalling Group, Institut für Kardiovaskuläre Physiologie (MD, EB, RB, IF), Johann Wolfgang Goethe Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, and Physiologisches Institut (TN, FVH), Justus Liebig Universität, D-35392 Giessen, Germany
Address correspondence to: Prof. Dr. Ingrid Fleming, Vascular Signalling group, Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, Tel: (+49)6963016972, D-60596 Frankfurt/Main, Fax: (+49)6963017668, Germany. E.mail: fleming{at}em.uni-frankfurt.de
Aims: Phosphorylation of forkhead box O (FoxO) transcription factors induces their nuclear exclusion and proteosomal degradation. Here we investigated the effect of fluid shear stress on FoxO1a in primary cultures of human endothelial cells and the kinases that regulate its phosphorylation.
Methods & Results: Shear stress (12 dynes/cm2) elicited the phosphorylation, nuclear exclusion and degradation of FoxO1a. Inhibition of Akt signaling using either a dominant negative mutant of Akt or downregulation of Gab1 largely failed to affect the shear stress-induced changes in FoxO1a, while a dominant negative AMP-activated protein kinase (AMPK) abrogated its shear stress-induced phosphorylation and degradation. Similar effects were observed using the AMPK inhibitor compound C. Moreover, in an in vitro assay, the AMPK directly phosphorylated FoxO1a. As FoxO1a regulates the expression of angiopoietin-2 (Ang-2), we determined the role of shear stress and the AMPK in this phenomenon. Not only did the dominant negative AMPK increase the expression of Ang-2 in cells maintained under static conditions, it also abrogated the shear stress-induced decrease in FoxO1a and Ang-2 protein levels. Functionally, Ang-2 sensitizes endothelial cells to the effects of tumor necrosis factor (TNF)-
, and dominant negative AMPK increased basal endothelial cell E-selectin expression and permeability as well as the increase induced by TNF-.
Conclusions: These data indicate that the AMPK activated by fluid shear stress is a novel regulator of FoxO1a phosphorylation and protein levels. Moreover, as the AMPK-dependent phosphorylation and degradation of FoxO1a attenuates Ang-2 expression and protects against the pro-inflammatory actions of TNF-, this kinase may be a useful target to prevent the progression of vascular diseases.
KEYWORDS Endothelial function; Energy metabolism; Mechanotransduction; Protein kinases
Time for primary review: 29 days
Current address: Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036 India.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  U. R. Jag, J. Zavadil, and F. M. Stanley Insulin Acts through FOXO3a to Activate Transcription of Plasminogen Activator Inhibitor Type 1 Mol. Endocrinol., October 1, 2009; 23(10): 1587 - 1602. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Fisslthaler and I. Fleming Activation and Signaling by the AMP-Activated Protein Kinase in Endothelial Cells Circ. Res., July 17, 2009; 105(2): 114 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Webler, U. R. Michaelis, R. Popp, E. Barbosa-Sicard, A. Murugan, J. R. Falck, B. Fisslthaler, and I. Fleming Epoxyeicosatrienoic acids are part of the VEGF-activated signaling cascade leading to angiogenesis Am J Physiol Cell Physiol, November 1, 2008; 295(5): C1292 - C1301. [Abstract] [Full Text] [PDF]
|
|