This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ho, F. M. Articles by Lin-Shiau, S. Y. Search for Related Content PubMed PubMed Citation Articles by Ho, F. M. Articles by Lin-Shiau, S. Y. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB GLUCOSE Related Collections Apoptosis

(Circulation. 2000;101:2618.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

High Glucose–Induced Apoptosis in Human Endothelial Cells Is Mediated by Sequential Activations of c-Jun NH₂-Terminal Kinase and Caspase-3

Feng M. Ho, MD; Shing H. Liu, PhD; Chiau S. Liau, MD; Por J. Huang, MD; Shoei Y. Lin-Shiau, PhD

From the Institute of Toxicology (F.M.H., S.H.L., S.Y.L-S.), Department of Internal Medicine (F.M.H., C.S.L., P.J.H.), College of Medicine, National Taiwan University, Taipei, and Department of Cardiology (F.M.H.), China Medical College, Taichung, Taiwan.

Correspondence to Shoei Y. Lin-Shiau, Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Rd, Taipei, 10018 Taiwan.

Background—Diabetes mellitus causes multiple cardiovascular complications. High glucose can induce reactive oxygen species and apoptosis in endothelial cells. Little is known about the molecular mechanisms in high glucose–induced endothelial cell apoptosis.

Methods and Results—We elucidated the signaling pathway of high glucose–induced apoptosis in human umbilical vein endothelial cells (HUVECs). HUVECs were treated with media containing 5.5, 19, or 33 mmol/L of glucose in the presence or absence of an antioxidant, ascorbic acid. The level of intracellular H₂O₂ was measured by flow cytometry. For detection of apoptosis, the cell death detection ELISA assay and the morphological Hoechst staining were used. High glucose was capable of inducing the activity of c-Jun NH₂-terminal kinase (JNK) but not extracellular signal–regulated kinase 1/2 or p38 mitogen-activated protein kinase during the treatment periods, as evidenced by immunocomplex kinase assay. Moreover, we found that the interleukin 1ß–converting enzyme (ICE)/CED-3 family protease (caspase-3) became activated in high glucose–induced apoptosis. Caspase-3/CPP32–specific inhibitor, Ac-DEVD-CHO, could inhibit high glucose–induced apoptosis. Furthermore, we found that JNK1 specific antisense oligonucleotide could suppress caspase-3 activity but not affect H₂O₂ generation and could block apoptosis induced by high glucose. Also, H₂O₂ generation, JNK activity, caspase-3 activity, and the subsequent apoptosis induced by high glucose could be suppressed by ascorbic acid.

Conclusions—The present study indicates that reactive oxygen species induced by high glucose may be involved in JNK activation, which in turn triggers the caspase-3 that facilitates the apoptosis in HUVECs.

Key Words: glucose • endothelium • cells • apoptosis • JNK • ICE • caspase

This article has been cited by other articles:

				Q. Huang and N. Sheibani High glucose promotes retinal endothelial cell migration through activation of Src, PI3K/Akt1/eNOS, and ERKs Am J Physiol Cell Physiol, December 1, 2008; 295(6): C1647 - C1657. [Abstract] [Full Text] [PDF]

				I. Tchivilev, N. R. Madamanchi, A. E. Vendrov, X.-L. Niu, and M. S. Runge Identification of a Protective Role for Protein Phosphatase 1c{gamma}1 against Oxidative Stress-induced Vascular Smooth Muscle Cell Apoptosis J. Biol. Chem., August 8, 2008; 283(32): 22193 - 22205. [Abstract] [Full Text] [PDF]

				E. Favaro, I. Miceli, B. Bussolati, M. Schimitt-Ney, P. Cavallo Perin, G. Camussi, and M. M. Zanone Hyperglycemia Induces Apoptosis of Human Pancreatic Islet Endothelial Cells: Effects of Pravastatin on the Akt Survival Pathway Am. J. Pathol., August 1, 2008; 173(2): 442 - 450. [Abstract] [Full Text] [PDF]

				W. Zhang, X.-H. Wang, S.-F. Chen, G.-P. Zhang, N. Lu, R.-M. Hu, and H.-M. Jin Biphasic response of endothelial progenitor cell proliferation induced by high glucose and its relationship with reactive oxygen species J. Endocrinol., June 1, 2008; 197(3): 463 - 470. [Abstract] [Full Text] [PDF]

				G. Spinetti, N. Kraenkel, C. Emanueli, and P. Madeddu Diabetes and vessel wall remodelling: from mechanistic insights to regenerative therapies Cardiovasc Res, May 1, 2008; 78(2): 265 - 273. [Abstract] [Full Text] [PDF]

				M. F. Chowdhry, H. A. Vohra, and M. Galinanes Diabetes increases apoptosis and necrosis in both ischemic and nonischemic human myocardium: Role of caspases and poly-adenosine diphosphate-ribose polymerase J. Thorac. Cardiovasc. Surg., July 1, 2007; 134(1): 124 - 131. [Abstract] [Full Text] [PDF]

				R. Marfella, C. Di Filippo, A. Baldi, M. Siniscalchi, F. C. Sasso, B. Crescenzi, F. Cirillo, G. F. Nicoletti, F. D'Andrea, G. Chiorazzo, et al. The Vascular Smooth Muscle Cells Apoptosis in Asymptomatic Diabetic Carotid Plaques: Role of Glycemic Control J. Am. Coll. Cardiol., May 16, 2006; 47(10): 2118 - 2120. [Full Text] [PDF]

				J. Zhou, B. K. Deo, K. Hosoya, T. Terasaki, I. G. Obrosova, F. C. Brosius III, and A. K. Kumagai Increased JNK Phosphorylation and Oxidative Stress in Response to Increased Glucose Flux through Increased GLUT1 Expression in Rat Retinal Endothelial Cells Invest. Ophthalmol. Vis. Sci., September 1, 2005; 46(9): 3403 - 3410. [Abstract] [Full Text] [PDF]

				M. L. Sheu, F. M. Ho, R. S. Yang, K. F. Chao, W. W. Lin, S. Y. Lin-Shiau, and S.-H. Liu High Glucose Induces Human Endothelial Cell Apoptosis Through a Phosphoinositide 3-Kinase-Regulated Cyclooxygenase-2 Pathway Arterioscler. Thromb. Vasc. Biol., March 1, 2005; 25(3): 539 - 545. [Abstract] [Full Text] [PDF]

				F. Andreozzi, C. D'Alessandris, M. Federici, E. Laratta, S. Del Guerra, S. Del Prato, P. Marchetti, R. Lauro, F. Perticone, and G. Sesti Activation of the Hexosamine Pathway Leads to Phosphorylation of Insulin Receptor Substrate-1 on Ser307 and Ser612 and Impairs the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Insulin Biosynthetic Pathway in RIN Pancreatic {beta}-Cells Endocrinology, June 1, 2004; 145(6): 2845 - 2857. [Abstract] [Full Text] [PDF]

				M. Galinanes and A. G Fowler Role of clinical pathologies in myocardial injury following ischaemia and reperfusion Cardiovasc Res, February 15, 2004; 61(3): 512 - 521. [Abstract] [Full Text] [PDF]

				S.-R. Lee and E. H. Lo Interactions Between p38 Mitogen-Activated Protein Kinase and Caspase-3 in Cerebral Endothelial Cell Death After Hypoxia-Reoxygenation Stroke, November 1, 2003; 34(11): 2704 - 2709. [Abstract] [Full Text] [PDF]

				S. McGinn, S. Saad, P. Poronnik, and C. A. Pollock High glucose-mediated effects on endothelial cell proliferation occur via p38 MAP kinase Am J Physiol Endocrinol Metab, October 1, 2003; 285(4): E708 - E717. [Abstract] [Full Text] [PDF]

				S. S.M. Chung, E. C.M. Ho, K. S.L. Lam, and S. K. Chung Contribution of Polyol Pathway to Diabetes-Induced Oxidative Stress J. Am. Soc. Nephrol., August 1, 2003; 14(90003): S233 - 236. [Abstract] [Full Text] [PDF]

				J. L. Evans, I. D. Goldfine, B. A. Maddux, and G. M. Grodsky Are Oxidative Stress-Activated Signaling Pathways Mediators of Insulin Resistance and {beta}-Cell Dysfunction? Diabetes, January 1, 2003; 52(1): 1 - 8. [Abstract] [Full Text] [PDF]

				S. G. Park, Y.-S. Kang, Y. H. Ahn, S. H. Lee, K.-R. Kim, K.-W. Kim, G. Y. Koh, Y.-G. Ko, and S. Kim Dose-dependent Biphasic Activity of tRNA Synthetase-associating Factor, p43, in Angiogenesis J. Biol. Chem., November 15, 2002; 277(47): 45243 - 45248. [Abstract] [Full Text] [PDF]

				J. L. Evans, I. D. Goldfine, B. A. Maddux, and G. M. Grodsky Oxidative Stress and Stress-Activated Signaling Pathways: A Unifying Hypothesis of Type 2 Diabetes Endocr. Rev., October 1, 2002; 23(5): 599 - 622. [Abstract] [Full Text] [PDF]

				T. Aoyama, G. Takemura, R. Maruyama, K.-i. Kosai, T. Takahashi, M. Koda, K. Hayakawa, Y. Kawase, S. Minatoguchi, and H. Fujiwara Molecular mechanisms of non-apoptosis by Fas stimulation alone versus apoptosis with an additional actinomycin D in cultured cardiomyocytes Cardiovasc Res, September 1, 2002; 55(4): 787 - 798. [Abstract] [Full Text] [PDF]

				P.B. Sugerman, N.W. Savage, L.J. Walsh, Z.Z. Zhao, X.J. Zhou, A. Khan, G.J. Seymour, and M. Bigby THE PATHOGENESIS OF ORAL LICHEN PLANUS Critical Reviews in Oral Biology & Medicine, July 1, 2002; 13(4): 350 - 365. [Abstract] [Full Text] [PDF]

				G. Bifulco, C. Di Carlo, M. Caruso, F. Oriente, A. Di Spiezio Sardo, P. Formisano, F. Beguinot, and C. Nappi Glucose Regulates Insulin Mitogenic Effect by Modulating SHP-2 Activation and Localization in JAr Cells J. Biol. Chem., June 28, 2002; 277(27): 24306 - 24314. [Abstract] [Full Text] [PDF]

				J. Chen, S. V. Brodsky, D. M. Goligorsky, D. J. Hampel, H. Li, S. S. Gross, and M. S. Goligorsky Glycated Collagen I Induces Premature Senescence-Like Phenotypic Changes in Endothelial Cells Circ. Res., June 28, 2002; 90(12): 1290 - 1298. [Abstract] [Full Text] [PDF]

				L. Cai, W. Li, G. Wang, L. Guo, Y. Jiang, and Y. J. Kang Hyperglycemia-Induced Apoptosis in Mouse Myocardium: Mitochondrial Cytochrome c-Mediated Caspase-3 Activation Pathway Diabetes, June 1, 2002; 51(6): 1938 - 1948. [Abstract] [Full Text] [PDF]

				Q.-B. She, N. Chen, A. M. Bode, R. A. Flavell, and Z. Dong Deficiency of c-Jun-NH2-terminal Kinase-1 in Mice Enhances Skin Tumor Development by 12-O-Tetradecanoylphorbol-13-Acetate Cancer Res., March 1, 2002; 62(5): 1343 - 1348. [Abstract] [Full Text] [PDF]

				T. Tawadros, A. Formenton, J. Dudler, N. Thompson, P. Nicod, H.-J. Leisinger, G. Waeber, and J.-A. Haefliger The scaffold protein IB1/JIP-1 controls the activation of JNK in rat stressed urothelium J. Cell Sci., January 15, 2002; 115(2): 385 - 393. [Abstract] [Full Text] [PDF]

				Y. Ido, D. Carling, and N. Ruderman Hyperglycemia-Induced Apoptosis in Human Umbilical Vein Endothelial Cells: Inhibition by the AMP-Activated Protein Kinase Activation Diabetes, January 1, 2002; 51(1): 159 - 167. [Abstract] [Full Text] [PDF]

				L. Rossig, J. Hoffmann, B. Hugel, Z. Mallat, A. Haase, J.-M. Freyssinet, A. Tedgui, A. Aicher, A. M. Zeiher, and S. Dimmeler Vitamin C Inhibits Endothelial Cell Apoptosis in Congestive Heart Failure Circulation, October 30, 2001; 104(18): 2182 - 2187. [Abstract] [Full Text] [PDF]

				F. Fiordaliso, A. Leri, D. Cesselli, F. Limana, B. Safai, B. Nadal-Ginard, P. Anversa, and J. Kajstura Hyperglycemia Activates p53 and p53-Regulated Genes Leading to Myocyte Cell Death Diabetes, October 1, 2001; 50(10): 2363 - 2375. [Abstract] [Full Text]

				M. Zanetti, R. M. Zwacka, J. F. Engelhardt, Z. S. Katusic, and T. O'Brien Superoxide Anions and Endothelial Cell Proliferation in Normoglycemia and Hyperglycemia Arterioscler. Thromb. Vasc. Biol., February 1, 2001; 21(2): 195 - 200. [Abstract] [Full Text] [PDF]

				M. M. Kavurma, F. S. Santiago, E. Bonfoco, and L. M. Khachigian Sp1 Phosphorylation Regulates Apoptosis via Extracellular FasL-Fas Engagement J. Biol. Chem., February 9, 2001; 276(7): 4964 - 4971. [Abstract] [Full Text] [PDF]