NDLI: Hyperglycemia alters PI3k and Akt signaling and leads to endothelial cell proliferative dysfunction.

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Hyperglycemia alters PI3k and Akt signaling and leads to endothelial cell proliferative dysfunction.

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Hyperglycemia alters PI3k and Akt signaling and leads to endothelial cell proliferative dysfunction.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Varma, Shubha Lal, Brajesh K. Zheng, Ruifang Breslin, Jerome W. Saito, Satoshi Pappas, Peter J. Hobson, Robert W. Durán, Walter N.
Description	Country affiliation: United States Author Affiliation: Varma S ( Department of Surgery, UMDNJ-New Jersey Medical School, 185 S. Orange Ave., Newark, NJ 07101, USA.)
Abstract	Diabetes mellitus is a major risk factor for the development of vascular complications. We hypothesized that hyperglycemia decreases endothelial cell (EC) proliferation and survival via phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathways. We cultured human umbilical vein ECs (HUVEC) in 5, 20, or 40 mM d-glucose. Cells grown in 5, 20, and 40 mM mannitol served as a control for osmotic effects. We measured EC proliferation for up to 15 days. We assessed apoptosis by annexin V and 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. ECs in media containing 5 mM d-glucose (control) exhibited log-phase growth on days 7-10. d-Glucose at 20 and 40 mM significantly decreased proliferation versus control (P < 0.05 for both), whereas mannitol did not impair EC proliferation. Apoptosis increased significantly in HUVEC exposed to 40 mM d-glucose. d-Glucose at 40 mM significantly decreased tyrosine-phosphorylated PI3k, threonine 308-phosphorylated-Akt, and Akt activity relative to control 5 mM d-glucose. Pharmacological inhibition of PI3k-Akt resulted in a dose-dependent decrease in EC proliferation. Transfection with a constitutively active Akt mutant protected ECs by enhancing proliferation when grown in 20 and 40 mM d-glucose. We conclude that d-glucose regulates Akt signaling through threonine phosphorylation of Akt and that hyperglycemia-impaired PI3k-Akt signaling may promote EC proliferative dysfunction in diabetes.
File Format	HTM / HTML
ISSN	03636135
e-ISSN	15221539
Journal	AJP: Heart and Circulatory Physiology
Issue Number	4
Volume Number	289
Language	English
Publisher	American Physiological Society
Publisher Date	2005-10-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Physiology Discipline Cardiology Endothelium, Vascular Enzymology Hyperglycemia Metabolism Pathology Phosphatidylinositol 3-kinases Protein-serine-threonine Kinases Proto-oncogene Proteins Signal Transduction Physiology Cell Division Drug Effects Cell Survival Cells, Cultured Cytology Glucose Pharmacology Proto-oncogene Proteins C-akt Umbilical Veins Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Research Support, U.s. Gov't, P.h.s.
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Cardiology and Cardiovascular Medicine

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