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High Glucose via Peroxynitrite Causes Tyrosine Nitration and Inactivation of Prostacyclin Synthase That Is Associated With Thromboxane/Prostaglandin H2 Receptor–Mediated Apoptosis and Adhesion Molecule Expression in Cultured Human Aortic Endothelial Cells

Diabetes (New York, N.Y.), 2002-01, Vol.51 (1), p.198-203 [Peer Reviewed Journal]

2002 INIST-CNRS ;ISSN: 0012-1797 ;EISSN: 1939-327X ;DOI: 10.2337/diabetes.51.1.198 ;PMID: 11756341 ;CODEN: DIAEAZ

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  • Title:
    High Glucose via Peroxynitrite Causes Tyrosine Nitration and Inactivation of Prostacyclin Synthase That Is Associated With Thromboxane/Prostaglandin H2 Receptor–Mediated Apoptosis and Adhesion Molecule Expression in Cultured Human Aortic Endothelial Cells
  • Author: ZOU, Ming-Hui ; CHAOMEI SHI ; COHEN, Richard A
  • Subjects: Biological and medical sciences
  • Is Part Of: Diabetes (New York, N.Y.), 2002-01, Vol.51 (1), p.198-203
  • Description: High Glucose via Peroxynitrite Causes Tyrosine Nitration and Inactivation of Prostacyclin Synthase That Is Associated With Thromboxane/Prostaglandin H 2 Receptor–Mediated Apoptosis and Adhesion Molecule Expression in Cultured Human Aortic Endothelial Cells Ming-Hui Zou , Chaomei Shi and Richard A. Cohen Vascular Biology Unit, Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts Abstract Loss of the modulatory role of the endothelium may be a critical initial factor in the development of diabetic vascular diseases. Exposure of human aortic endothelial cells (HAECs) to high glucose (30 or 44 mmol/l) for 7–10 days significantly increased the release of superoxide anion in response to the calcium ionophore A23187. Nitrate, a breakdown product of peroxynitrite (ONOO − ), was substantially increased in parallel with a decline in cyclic guanosine monophosphate (GMP). Using immunochemical techniques and high-performance liquid chromatography, an increase in tyrosine nitration of prostacyclin (PGI 2 ) synthase (PGIS) associated with a decrease in its activity was found in cells exposed to high glucose. Both the increase in tyrosine nitration and the decrease in PGIS activity were lessened by decreasing either nitric oxide or superoxide anion, suggesting that ONOO − was responsible. Furthermore, SQ29548, a thromboxane/prostaglandin (PG) H 2 (TP) receptor antagonist, significantly reduced the increased endothelial cell apoptosis and the expression of soluble intercellular adhesion molecule-1 that occurred in cells exposed to high glucose, without affecting the decrease in PGIS activity. Thus, exposure of HAECs to high glucose increases formation of ONOO − , which causes tyrosine nitration and inhibition of PGIS. The shunting of arachidonic acid to the PGI 2 precursor PGH 2 or other eicosanoids likely results in TP receptor stimulation. These observations can explain several abnormalities in diabetes, including 1 ) increased free radicals, 2 ) decreased bioactivity of NO, 3 ) PGI 2 deficiency, and 4 ) increased vasoconstriction, endothelial apoptosis, and inflammation via TP receptor stimulation. Footnotes Address correspondence and reprint requests to Ming-Hui Zou, MD, PhD, Vascular Biology Unit X708, Boston University School of Medicine, 650 Albany St., Boston, MA 02118. E-mail: mhzou{at}medicine.bu.edu . Received for publication 10 May 2001 and accepted in revised form 12 October 2001. ELISA, enzyme-linked immunosorbent assay; GMP, guanosine monophosphate; HAEC, human aortic endothelial cell; l -NAME, N G -monomethyl- l -arginine methyl ester; NO, nitric oxide; ONOO − , peroxynitrite; PBS, phosphate-buffered saline; PG, prostaglandin; PGI 2 , prostacyclin; PGIS, PGI 2 synthase; sICAM, soluble intercellular adhesion molecule; SOD, superoxide dismutase; TP, thromboxane/PGH 2 ; TxA 2, thromboxane.
  • Publisher: Alexandria, VA: American Diabetes Association
  • Language: English
  • Identifier: ISSN: 0012-1797
    EISSN: 1939-327X
    DOI: 10.2337/diabetes.51.1.198
    PMID: 11756341
    CODEN: DIAEAZ
  • Source: Alma/SFX Local Collection
    ProQuest Central
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