The Role of Protein Kinase C Activation in the Pathogenesis of Diabetic Vascular Complications

Abstract

Many vascular diseases in diabetes are known to be associated with the activation of the diacylglycerol (OAG)protein kinase C (PKC) pathway. The major source of OAG that is elevated in diabetes is de novo synthesis from glycolytic intermediates. Among the various PKC isoforms, the β-isoform has been shown to be persistently activated in diabetic animals. Multiple lines of evidence have shown that many vascular alterations in diabetes such as a decrease in the activity of Na+-K+ -adenosine triphosphatase (Na+-K+-ATPase), and increases in extracellular matrix, cytokines, permeability, contractility, and cell proliferation -are caused by activation of PKC. Inhibition of PKC by two different kinds of PKC inhibitors, LY333531, a selective PKC-β-isoform inhibitor, and d-α-tocopherol, were able to prevent or reverse the various vascular dysfunctions in diabetic rats. These results have also provided in vivo evidence that OAG-PKC activation could be responsible for the hyperglycemia-induced vascular dysfunctions in diabetes. Clinical studies are now being performed to clarify the pathogenic roles of the OAG-PKC pathway in developing vascular complications in diabetic patients.