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PKC-β activation inhibits IL-18-binding protein causing endothelial dysfunction and diabetic atherosclerosis
Marie-Claude Durpès1, Catherine Morin1, Judith Paquin-Veillet1
1Research Center of the Centre Hospitalier Universitaire de Sherbrooke and Division of Endocrinology, Department of Medicine, Université de Sherbrooke, 3001 12e Avenue Nord, QC, Canada J1H 5N4.
Cardiovascular Research
|March 27, 2015
Summary
Protein kinase C beta (PKC-β) activation in diabetes disrupts the IL-18/IL-18BP pathway, increasing vascular cell adhesion molecule-1 (VCAM-1) and monocyte adhesion, accelerating atherosclerosis. Inhibition of PKC-β prevents this process.
Area of Science:
- Cardiovascular Biology
- Immunology
- Metabolic Diseases
Background:
- Diabetes mellitus (DM) accelerates atherosclerosis, linked to elevated pro-inflammatory Interleukin-18 (IL-18).
- Protein kinase C beta (PKC-β) inhibition shows promise in mitigating diabetic atherosclerosis.
- The specific role of PKC-β in the IL-18/IL-18-binding protein (IL-18BP) pathway in diabetes remains unexplored.
Purpose of the Study:
- To investigate the mechanism by which PKC-β activation influences the IL-18/IL-18BP pathway in diabetic atherosclerosis.
- To determine the effect of PKC-β inhibition on endothelial dysfunction and monocyte adhesion in diabetes.
Main Methods:
- Apoe(-/-) mice were made diabetic and treated with ruboxistaurin (RBX), a PKC-β inhibitor.
- Atherosclerotic plaque composition, IL-18BP expression, and VCAM-1 were quantified.
- Endothelial cells and macrophages were exposed to high glucose and palmitate conditions with or without IL-18, and treated with RBX or IL-18 neutralizing antibody.
Main Results:
- Diabetic mice showed increased plaque formation, macrophage infiltration, and reduced aortic IL-18BP, which RBX treatment prevented.
- High glucose and palmitate increased IL-18 in macrophages and decreased IL-18BP in endothelial cells, upregulating VCAM-1 and monocyte adhesion.
- RBX, siRNA, and IL-18 neutralizing antibody inhibited VCAM-1 expression and monocyte adherence.
Conclusions:
- PKC-β activation promotes endothelial dysfunction in diabetes via IL-18/IL-18BP pathway dysregulation.
- This mechanism leads to increased VCAM-1, monocyte adhesion, and accelerated atherosclerotic plaque formation.
- Targeting PKC-β may offer a therapeutic strategy for diabetic atherosclerosis.
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