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.
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
J Y
JY
Park
S W
SW
Ha
G L
GL
King
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003925:Diabetic Angiopathies / Q000378:metabolism / Q000503:physiopathology*; D019852:Diacylglycerol Kinase / Q000378:metabolism; D004789:Enzyme Activation; D006439:Hemodynamics; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*
D001786:Blood Glucose; D007527:Isoenzymes; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C