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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:539.)
© 2005 American Heart Association, Inc.

Vascular Biology

High Glucose Induces Human Endothelial Cell Apoptosis Through a Phosphoinositide 3-Kinase–Regulated Cyclooxygenase-2 Pathway

Meei Ling Sheu; Feng Ming Ho; Rong Sen Yang; Kuo Fang Chao; Wan Wan Lin; Shoei Yn Lin-Shiau; Shing-Hwa Liu

From the Institutes of Toxicology (M.L.S., K.F.C., S.Y.L.S., S.H.L.) and Pharmacology (S.Y.L.S., W.W.L.), and the Department of Orthopedics (R.S.Y.), College of Medicine, National Taiwan University, Taipei; and the Department of Internal Medicine (F.M.H.), Tao-Yuan General Hospital, Taoyan, Taiwan.

Correspondence to Shing-Hwa Liu, PhD, Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Rd, Taipei, 10043, Taiwan. E-mail shliu{at}ha.mc.ntu.edu.tw

Objectives— Diabetes mellitus causes endothelial dysfunction. The precise molecular mechanisms by which hyperglycemia causes apoptosis in endothelial cells are not yet well understood. The aim of this study was to explore the role of cyclooxygenase-2 (COX-2) and the possible involvement of phosphoinositide 3-kinase (PI3K) signaling in high glucose (HG)–induced apoptosis in human umbilical vein endothelial cells (HUVECs).

Methods and Results— For detection of apoptosis, the morphological Hoechst staining and Annexin V/propidium iodide staining were used. Glucose upregulated COX-2 protein expression, which was associated with the induction of prostaglandin (PG) E₂ (PGE₂), caspase-3 activity, and apoptosis. Unexpectedly, we found that PI3K inhibitors could suppress COX-2 expression, PGE₂ production, caspase-3 activity, and the subsequent apoptosis under HG condition. Glucose-induced activation of PI3K resulted in the downstream effector Akt phosphorylation. PI3K inhibitors effectively attenuated the intracellular reactive oxygen species (ROS) generation and nuclear factor B (NF-B) activation. Blocking the PI3K and Akt activities with the dominant-negative vectors greatly diminished the HG-triggered NF-B activation and COX-2 expression and apoptosis.

Conclusions— These results suggest that HG, via PI3K/Akt signaling, induces NF-B–related upregulation of COX-2, which in turn triggers the caspase-3 activity that facilitates HUVEC apoptosis. Also, HG may cause ROS generation in HUVECs through a PI3K/Akt–dependent pathway.

We demonstrated for the first time that the signaling pathway of PI3K/Akt–regulated upregulation of COX-2 was involved in glucose-induced apoptosis in human endothelial cells. These findings were supported by results that PI3K inhibition prevented the glucose-caused COX-2–mediated PGE₂ production, which subsequently led to the induction of caspase-3 activity and apoptosis.

Key Words: glucose • endothelium • cells • apoptosis

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