Protein kinase C β inhibition: a novel therapeutic strategy for diabetic microangiopathy

Abstract

Biochemical mechanisms involved in hyperglycaemia-induced vascular damage include alterations in cellular signalling by activation of protein kinase C (PKC). Twelve isoforms of PKC have been characterised according to their structure and co-factor requirements. Activation of PKC is mediated primarily through increased release of diacylglycerol (DAG). Adverse effects of PKC and DAG on vascular function include increased permeability, endothelial cell activation, altered blood flow, leukocyte adhesion and abnormal growth factor signalling. A highly selective and orally active PKC-β isoform-selective inhibitor, ruboxistaurin, has been developed. Initial studies suggest that this agent decreased the development of sight-threatening macular oedema and the occurrence of visual loss. It did not, however, prevent the progression of diabetic retinopathy.