The role of protein kinase C activation in the pathogenesis of diabetic vascular complications.

Many vascular diseases in diabetes are known to be associated with the activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway. The major source of DAG that is elevated in diabetes is de novo synthesis from glycolytic intermediates. Among the various PKC isoforms, the beta-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-beta-isoform inhibitor, and d-alpha-tocopherol, were able to prevent or reverse the various vascular dysfunctions in diabetic rats. These results have also provided in vivo evidence that DAG-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 DAG-PKC pathway in developing vascular complications in diabetic patients.