Key result
PKCbeta2 inhibition prevents a ~72% high-glucose-induced increase in endothelial VCAM-1 expression.
Why the study?
Enhanced expression of adhesion molecules by the endothelium may contribute to vascular damage during acute hyperglycemia in diabetics and nondiabetic patients with stress hyperglycemia.
Does selective inhibition of PKCbeta2 prevent high glucose-induced VCAM-1 expression in human aortic endothelial cells?
Does selective inhibition of PKCbeta2 prevent high glucose-induced VCAM-1 expression in human aortic endothelial cells?
Selective inhibition of PKCbeta2 prevents glucose-induced upregulation of VCAM-1 in human endothelial cells, suggesting a potential therapeutic target for endothelial dysfunction in acute hyperglycemia.
Answers are grounded in this paper and cite their sources.
PKCβ2 inhibition may counter hyperglycemia-driven endothelial activation; extends mechanistic evidence toward targeted therapies in diabetic vascular disease.
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 Cbeta2 (PKCbeta2) 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 PKCbeta, reflecting activation of this enzyme. The nonselective inhibitor of PKCbeta1 and PKCbeta2 isoforms LY379196, as well as CGP53353, a highly selective inhibitor of PKCbeta2, prevented in a dose-dependent manner upregulation of VCAM-1. Incubation with high glucose was associated with increased PKCbeta2 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-kappaB, IkappaBalpha, leading to its enhanced binding activity. Selective inhibition of PKCbeta abolished IkappaBalpha 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, PKCbeta2-selective inhibitors may be promising drugs for treatment of endothelial dysfunction during acute hyperglycemia and possibly in diabetes.
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Kouroedov et al. (2004) studied Endothelial dysfunction during acute hyperglycemia. High glucose and selective PKCbeta2 inhibitors (LY379196, CGP53353) vs. Control was evaluated on Vascular cell adhesion molecule (VCAM)-1 protein expression (p=<0.01). Incubation of human aortic endothelial cells with high glucose significantly increased VCAM-1 protein expression (172% versus control; P<0.01), which was prevented by selective PKCbeta2 inhibition.
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