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Am J Physiol Heart Circ Physiol (June 17, 2005). doi:10.1152/ajpheart.01088.2004
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Submitted on October 25, 2004
Accepted on June 1, 2005

Hyperglycemia Alters PI3k and Akt Signaling and Leads to Endothelial Cell Proliferative Dysfunction

Shubha Varma1, Brajesh K Lal2, Ruifang Zheng1, Jerome W Breslin3, Satoshi Saito2, Peter J Pappas2, Robert W Hobson II2, and Walter N Duran2*

1 Surgery, UMDNJ-New Jersey Medical School, Newark, NJ, USA
2 Pharmacology & Physiology, UMDNJ-New Jersey Medical School, Newark, NJ, USA; Surgery, UMDNJ-New Jersey Medical School, Newark, NJ, USA
3 Pharmacology & Physiology, UMDNJ-New Jersey Medical School, Newark, NJ, USA

* To whom correspondence should be addressed. E-mail: duran{at}umdnj.edu.

Diabetes mellitus is a major risk factor for the development of vascular complications. We hypothesized that hyperglycemia decreases EC proliferation and survival, via phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathways. We cultured human umbilical vein endothelial cells (HUVEC) in 5, 20 or 40 mM D-glucose. Cells grown in 5, 20 and 40 mM mannitol served as control for osmotic effects. We measured endothelial cell proliferation for up to 15 days. We assessed apoptosis by Annexin-V/propidium iodide staining and flow-cytometry; analyzed cell lysates obtained on culture day 8, for total and phosphorylated PI3k and Akt by Western blot analysis; and measured Akt kinase activity using a GSK fusion protein. HUVEC proliferation was also tested in the presence of pharmacological inhibitors of PI3k-Akt (wortmannin and LY294002) and after transfection with a constitutively active Akt mutant. Endothelial cells in media containing 5 mM D-glucose (control) exhibited log-phase growth on days 7 to 10. D-glucose at 20 and 40 mM significantly decreased proliferation vs. control (p<0.05 for both), while mannitol did not impair EC proliferation. Apoptosis increased significantly in HUVEC exposed to 40 mM D-glucose. D-Glucose at 40mM significantly decreased tyrosine phosphorylated PI3k, threonine 308-phosphorylated-Akt, and Akt activity relative to control 5mM D-glucose. Pharmacological inhibition of PI3k-Akt resulted in a dose-dependent decrease in EC proliferation. Transfection with a constitutively active Akt mutant protected EC by enhancing proliferation when grown in 20 and 40 mM glucose. We conclude that D-glucose regulates Akt signaling through threonine-phosphorylation of Akt and that hyperglycemia-impaired PI3k/Akt signaling may promote endothelial cell proliferative dysfunction in diabetes.




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