High glucose augments the angiotensin II-induced activation of JAK2 in vascular smooth muscle cells via the polyol pathway

Sean Shaw, Xiaodan Wang, Heather Redd, Gwendolyn D. Alexander, Carlos M. Isales, Mario B. Marrero

Research output: Contribution to journalArticle

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Abstract

Angiotensin II (Ang II), protein kinase C (PKC), reactive oxygen species (ROS) generated by NADPH oxidase, the activation of Janus kinase 2 (JAK2), and the polyol pathway play important parts in the hyperproliferation of vascular smooth muscle cells (VSMC), a characteristic feature of diabetic macroangiopathy. The precise mechanism, however, remains unclear. This study investigated the relation between the polyol pathway, PKC-β, ROS, JAK2, and Ang II in the development of diabetic macroangiopathy. VSMC cultured in high glucose (HG; 25 mM) showed significant increases in the tyrosine phosphorylation of JAK2, production of ROS, and proliferation activities when compared with VSMC cultured in normal glucose (5.5 mM (NG)). Both the aldose reductase specific inhibitor (zopolrestat) or transfection with aldose reductase antisense oligonucleotide blocked the phosphorylation of JAK2, the production of ROS, and proliferation of VSMC induced by HG, but it had no effect on the Ang II-induced activation of these parameters in both NG and HG. However, transfection with PKC-β antisense oligonucleotide, preincubation with a PKC-β-specific inhibitor (LY379196) or apocynin (NADPH oxidase-specific inhibitor), or electroporation of NADPH oxidase antibodies blocked the Ang II-induced JAK2 phosphorylation, production of ROS, and proliferation of VSMC in both NG and HG. These observations suggest that the polyol pathway hyperactivity induced by HG contributes to the development of diabetic macroangiopathy through a PKC-β-ROS activation of JAK2.

Original languageEnglish (US)
Pages (from-to)30634-30641
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number33
DOIs
StatePublished - Aug 15 2003

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Janus Kinase 2
Vascular Smooth Muscle
Angiotensin II
Smooth Muscle Myocytes
Muscle
Reactive Oxygen Species
Protein Kinase C
Chemical activation
Cells
Glucose
Phosphorylation
NADPH Oxidase
Aldehyde Reductase
Antisense Oligonucleotides
5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate
Transfection
Electroporation
Tyrosine
polyol
Antibodies

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

High glucose augments the angiotensin II-induced activation of JAK2 in vascular smooth muscle cells via the polyol pathway. / Shaw, Sean; Wang, Xiaodan; Redd, Heather; Alexander, Gwendolyn D.; Isales, Carlos M.; Marrero, Mario B.

In: Journal of Biological Chemistry, Vol. 278, No. 33, 15.08.2003, p. 30634-30641.

Research output: Contribution to journalArticle

Shaw, Sean ; Wang, Xiaodan ; Redd, Heather ; Alexander, Gwendolyn D. ; Isales, Carlos M. ; Marrero, Mario B. / High glucose augments the angiotensin II-induced activation of JAK2 in vascular smooth muscle cells via the polyol pathway. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 33. pp. 30634-30641.
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