Published Online
on June 21, 2004

A more recent version of this article appeared on July 6, 2004

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Submitted on December 11, 2003
Revised on March 30, 2004
Accepted on April 2, 2004

Selective Inhibition of Protein Kinase C₂ Prevents Acute Effects of High Glucose on Vascular Cell Adhesion Molecule-1 Expression in Human Endothelial Cells

Alexei Kouroedov MD, Masato Eto MD, PhD, Hana Joch , Massimo Volpe MD, Thomas F. Lüscher MD, and Francesco Cosentino MD, PhD^*

From Cardiovascular Research, Institute of Physiology, University of Zürich and Cardiovascular Center, University Hospital, Zürich, Switzerland (A.K., M.E., H.J., T.F.L., F.C.); and the Division of Cardiology, 2nd Faculty of Medicine, University La Sapienza, Rome, and IRCCS Neuromed, Pozzilli, Italy (M.V., F.C.).

^* To whom correspondence should be addressed. E-mail: f_cosentino{at}hotmail.com.

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 C₂ (PKC₂) 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; P<0.01). Phorbol 12-myristate 13-acetate, a potent activator of PKC, mimicked the effect of high glucose on VCAM-1 expression. High glucose led to a rapid increase (181±22% versus control; P<0.01) of membrane-bound PKC, reflecting activation of this enzyme. The nonselective inhibitor of PKC₁ and PKC₂ isoforms LY379196, as well as CGP53353, a highly selective inhibitor of PKC₂, prevented in a dose-dependent manner upregulation of VCAM-1. Incubation with high glucose was associated with increased PKC₂ 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-B, IB, leading to its enhanced binding activity. Selective inhibition of PKC abolished IB 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, PKC₂-selective inhibitors may be promising drugs for treatment of endothelial dysfunction during acute hyperglycemia and possibly in diabetes.

Key words: diabetes mellitus • cell adhesion molecules • endothelium • inhibitors

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