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(Circulation. 2007;116:1585-1595.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Reactive Nitrogen Species Induced by Hyperglycemia Suppresses Akt Signaling and Triggers Apoptosis by Upregulating Phosphatase PTEN (Phosphatase and Tensin Homologue Deleted on Chromosome 10) in an LKB1-Dependent Manner

Ping Song, PhD; Yong Wu, MD, PhD; Jian Xu, PhD; Zhonglin Xie, MD, PhD; Yunzhou Dong, PhD; Miao Zhang, MD, PhD; Ming-Hui Zou, MD, PhD

From the Section of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City.

Correspondence to Ming-Hui Zou, MD, PhD, BSEB 325, Section of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104. E-mail ming-hui-zou{at}ouhsc.edu

Received May 22, 2007; accepted July 23, 2007.

Background— Oxidative stress plays a causal role in vascular injury in diabetes mellitus, but the mechanisms and targets remain poorly understood.

Methods and Results— Exposure of cultured human umbilical vein endothelial cells to either peroxynitrite (ONOO^–) or high glucose significantly inhibited both basal and insulin-stimulated Akt phosphorylation at Ser473 and Akt activity in parallel with increased apoptosis, phosphorylation, and activity of phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Furthermore, protein kinase B/Akt inhibition induced by ONOO^– or high glucose and apoptosis triggered by high glucose could be abolished by transfection of PTEN-specific small interfering RNA, suggesting that PTEN mediated the Akt inhibition by ONOO^–. In addition, exposure of human umbilical vein endothelial cells to ONOO^– or high glucose remarkably increased Ser428 phosphorylation of LKB1, a tumor suppressor. Interestingly, the ONOO^–-enhanced PTEN phosphorylation and Akt inhibition can be blocked by LKB1-specific small interfering RNA. Consistently, LKB1 phosphorylated PTEN at Ser380/Thr382/383 in vitro, suggesting that LKB1 might act as an upstream kinase for PTEN. Compared with nondiabetic mice, the levels of PTEN, LKB1-Ser428 phosphorylation, and 3-nitrotyrosine (a biomarker of ONOO^–) were significantly increased in the aortas of streptozotocin-induced diabetic mice, which was in parallel with a reduction in Akt-Ser473 phosphorylation and an increase in apoptosis. Furthermore, administration of PTEN-specific small interfering RNA suppressed diabetes-enhanced apoptosis and Akt inhibition. Finally, treatment with Tempol, a superoxide dismutase mimetic, and insulin, both of which reduced the ONOO^– formation, markedly reduced diabetes-enhanced LKB1-Ser428 phosphorylation, PTEN, and apoptosis in the endothelium of mouse aortas.

Conclusion— We conclude that hyperglycemia triggers apoptosis by inhibiting Akt signaling via ONOO^–-mediated LKB1-dependent PTEN activation.

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