Fluid Shear Stress Stimulates Phosphorylation of Akt in Human Endothelial Cells

Involvement in Suppression of Apoptosis

From the Department of Internal Medicine IV, Molecular Cardiology, University of Frankfurt, Frankfurt, Germany.

Correspondence to Andreas M. Zeiher, MD, Department of Internal Medicine IV, Division of Cardiology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail Zeiher{at}em.uni-frankfurt.de

Abstract—Fluid shear stress alters the morphology and function of the endothelium by activating several kinases. Furthermore, shear stress potently inhibits apoptosis of endothelial cells. Since activation of Akt kinase has been shown to prevent cell death, we investigated the effects of shear stress on Akt phosphorylation. To test the hypothesis that shear stress interacts with the Akt kinase pathway, human umbilical venous endothelial cells were exposed to laminar shear stress (15 dyne/cm²). Western blotting with specific antibodies against the phosphorylated Akt demonstrated a time-dependent stimulation of Akt phosphorylation by shear stress with a maximal increase up to 6-fold after 1 hour of shear stress exposure. The stimulation of Akt phosphorylation by shear stress thereby seemed to be mediated by the phosphoinositide 3-OH kinase (PI3K), as evidenced by the significant inhibition of shear stress–induced Akt phosphorylation by the PI3K inhibitors wortmannin (20 nmol/L) and Ly294002 (10 µmol/L). In addition, pharmacological inhibition of PI3K reduced the antiapoptotic effect of shear stress against growth factor depletion–induced apoptosis. Most important, overexpression of a dominant-negative Akt mutant significantly inhibited the apoptosis-suppressive effect of shear stress against serum depletion–induced apoptosis, thus indicating the direct involvement of shear stress–induced Akt phosphorylation for inhibition of endothelial cell apoptosis. These results define a novel shear stress–stimulated signal transduction pathway, namely, activation of the serine/threonine kinase Akt, which may contribute to the profound changes in endothelial morphology and function by shear stress.

Key Words: protein kinase B • growth factor • integrin • apoptosis • endothelial cell

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				F. Kim, B. Gallis, and M. A. Corson TNF-{alpha} inhibits flow and insulin signaling leading to NO production in aortic endothelial cells Am J Physiol Cell Physiol, May 1, 2001; 280(5): C1057 - C1065. [Abstract] [Full Text] [PDF]

				E. Chavakis, E. Dernbach, C. Hermann, U. F. Mondorf, A. M. Zeiher, and S. Dimmeler Oxidized LDL Inhibits Vascular Endothelial Growth Factor-Induced Endothelial Cell Migration by an Inhibitory Effect on the Akt/Endothelial Nitric Oxide Synthase Pathway Circulation, April 24, 2001; 103(16): 2102 - 2107. [Abstract] [Full Text] [PDF]

				L. Rossig, J. Haendeler, Z. Mallat, B. Hugel, J.-M. Freyssinet, A. Tedgui, S. Dimmeler, and A. M. Zeiher Congestive heart failure induces endothelial cell apoptosis: protective role of carvedilol J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2081 - 2089. [Abstract] [Full Text] [PDF]

				S. A. Fisher, B. L. Langille, and D. Srivastava Apoptosis During Cardiovascular Development Circ. Res., November 10, 2000; 87(10): 856 - 864. [Abstract] [Full Text] [PDF]

				H. Aebert, S. Kirchner, A. Keyser, D. E. Birnbaum, E. Holler, R. Andreesen, and G. Eissner Endothelial apoptosis is induced by serum of patients after cardiopulmonary bypass Eur. J. Cardiothorac. Surg., November 1, 2000; 18(5): 589 - 593. [Abstract] [Full Text] [PDF]

				C. Urbich, D. H. Walter, A. M. Zeiher, and S. Dimmeler Laminar Shear Stress Upregulates Integrin Expression : Role in Endothelial Cell Adhesion and Apoptosis Circ. Res., October 13, 2000; 87(8): 683 - 689. [Abstract] [Full Text] [PDF]

				F. Jung, J. Haendeler, C. Goebel, A. M. Zeiher, and S. Dimmeler Growth factor-induced phosphoinositide 3-OH kinase/Akt phosphorylation in smooth muscle cells: induction of cell proliferation and inhibition of cell death Cardiovasc Res, October 1, 2000; 48(1): 148 - 157. [Abstract] [Full Text] [PDF]

				M. Vasa, K. Breitschopf, A. M. Zeiher, and S. Dimmeler Nitric Oxide Activates Telomerase and Delays Endothelial Cell Senescence Circ. Res., September 29, 2000; 87(7): 540 - 542. [Full Text] [PDF]

				S. Dimmeler and A. M. Zeiher Endothelial Cell Apoptosis in Angiogenesis and Vessel Regression Circ. Res., September 15, 2000; 87(6): 434 - 439. [Abstract] [Full Text] [PDF]

				K. Irani Oxidant Signaling in Vascular Cell Growth, Death, and Survival : A Review of the Roles of Reactive Oxygen Species in Smooth Muscle and Endothelial Cell Mitogenic and Apoptotic Signaling Circ. Res., August 4, 2000; 87(3): 179 - 183. [Abstract] [Full Text] [PDF]

				K. Lin, P.-P. Hsu, B. P. Chen, S. Yuan, S. Usami, J. Y.-J. Shyy, Y.-S. Li, and S. Chien Molecular mechanism of endothelial growth arrest by laminar shear stress PNAS, July 30, 2000; (2000) 170282597. [Abstract] [Full Text]

				L. Sandirasegarane, R. Charles, N. Bourbon, and M. Kester NO regulates PDGF-induced activation of PKB but not ERK in A7r5 cells: implications for vascular growth arrest Am J Physiol Cell Physiol, July 1, 2000; 279(1): C225 - C235. [Abstract] [Full Text] [PDF]

				L. W. Kraiss, A. S. Weyrich, N. M. Alto, D. A. Dixon, T. M. Ennis, V. Modur, T. M. McIntyre, S. M. Prescott, and G. A. Zimmerman Fluid flow activates a regulator of translation, p70/p85 S6 kinase, in human endothelial cells Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1537 - H1544. [Abstract] [Full Text] [PDF]

				R. Golser, A. C. F. Gorren, A. Leber, P. Andrew, H.-J. Habisch, E. R. Werner, K. Schmidt, R. C. Venema, and B. Mayer Interaction of Endothelial and Neuronal Nitric-oxide Synthases with the Bradykinin B2 Receptor. BINDING OF AN INHIBITORY PEPTIDE TO THE OXYGENASE DOMAIN BLOCKS UNCOUPLED NADPH OXIDATION J. Biol. Chem., February 25, 2000; 275(8): 5291 - 5296. [Abstract] [Full Text] [PDF]

				K. S. Russell, M. P. Haynes, T. Caulin-Glaser, J. Rosneck, W. C. Sessa, and J. R. Bender Estrogen Stimulates Heat Shock Protein 90 Binding to Endothelial Nitric Oxide Synthase in Human Vascular Endothelial Cells. EFFECTS ON CALCIUM SENSITIVITY AND NO RELEASE J. Biol. Chem., February 18, 2000; 275(7): 5026 - 5030. [Abstract] [Full Text] [PDF]

				C. Hermann, B. Assmus, C. Urbich, A. M. Zeiher, and S. Dimmeler Insulin-Mediated Stimulation of Protein Kinase Akt : A Potent Survival Signaling Cascade for Endothelial Cells Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 402 - 409. [Abstract] [Full Text] [PDF]

				C. Urbich, M. Fritzenwanger, A. M. Zeiher, and S. Dimmeler Laminar Shear Stress Upregulates the Complement-Inhibitory Protein Clusterin : A Novel Potent Defense Mechanism Against Complement-Induced Endothelial Cell Activation Circulation, February 1, 2000; 101(4): 352 - 355. [Abstract] [Full Text] [PDF]