Selective inhibition of protein kinase Cβ2 prevents acute effects of high glucose on vascular cell adhesion molecule-1 expression in human endothelial cells

Alexei Kouroedov, Masato Eto, Hana Joch, Massimo Volpe, Thomas F. Lüscher, Francesco Cosentino

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Background - Enhanced expression of adhesion molecules by the endothelium may account for vascular damage in diabetics and nondiabetic patients who develop stress hyperglycemia during acute myocardial infarction. We analyzed the phosphorylation of protein kinase Cβ2 (PKCβ2) at serine/threonine residues, which may contribute to the endothelial dysfunction during acute hyperglycemia. Furthermore, this study was designed to investigate whether selective blockade of this regulatory mechanism may prevent the development of endothelial hyperadhesiveness. Methods and Results - Incubation of the human aortic endothelial cells with high glucose (22.2 mmol/L) resulted in significant increase of vascular cell adhesion molecule (VCAM)-1 protein expression (172±15% versus control; P1, and PKCβ2 isoforms LY379196, as well as CGP53353, a highly selective inhibitor of PKCβ2, prevented in a dose-dependent manner upregulation of VCAM-1. Incubation with high glucose was associated with increased PKCβ2 phosphorylation at the Ser-660 residue, and both LY379196 and CGP53353 prevented this event. Exposure of the cells to high glucose also reduced the protein level of the inhibitory subunit of nuclear factor-κB, IκBα, leading to its enhanced binding activity. Selective inhibition of PKCβ abolished IκBα degradation. Conclusions - Our findings demonstrate for the first time that phosphorylation of Ser-660 represents a selective regulatory mechanism for glucose-induced upregulation of VCAM-1. Therefore, PKCβ2- selective inhibitors may be promising drugs for treatment of endothelial dysfunction during acute hyperglycemia and possibly in diabetes.

Original languageEnglish
Pages (from-to)91-96
Number of pages6
JournalCirculation
Volume110
Issue number1
DOIs
Publication statusPublished - Jul 6 2004

Fingerprint

Vascular Cell Adhesion Molecule-1
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
Protein Kinases
Endothelial Cells
Hyperglycemia
Glucose
Phosphorylation
Up-Regulation
Threonine
Protein Kinase Inhibitors
Serine
Endothelium
Blood Vessels
Protein Isoforms
Proteins
Myocardial Infarction
Pharmaceutical Preparations
4,5-dianilinophthalimide
Therapeutics

Keywords

  • Cell adhesion molecules
  • Diabetes mellitus
  • Endothelium
  • Inhibitors

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Selective inhibition of protein kinase Cβ2 prevents acute effects of high glucose on vascular cell adhesion molecule-1 expression in human endothelial cells. / Kouroedov, Alexei; Eto, Masato; Joch, Hana; Volpe, Massimo; Lüscher, Thomas F.; Cosentino, Francesco.

In: Circulation, Vol. 110, No. 1, 06.07.2004, p. 91-96.

Research output: Contribution to journalArticle

Kouroedov, Alexei ; Eto, Masato ; Joch, Hana ; Volpe, Massimo ; Lüscher, Thomas F. ; Cosentino, Francesco. / Selective inhibition of protein kinase Cβ2 prevents acute effects of high glucose on vascular cell adhesion molecule-1 expression in human endothelial cells. In: Circulation. 2004 ; Vol. 110, No. 1. pp. 91-96.
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