Protein kinase C beta inhibition: A novel therapeutic strategy for diabetic microangiopathy.
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-beta 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.
Idris
Iskandar
I
John Peace Diabetes Centre, Kings Mill Hospital, Sherwood Hospitals NHS Trust, Sutton in Ashfield, Nottinghamshire, NG17 4JL, UK. iidris@aol.com
Donnelly
Richard
R
D000818:Animals; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D007004:Hypoglycemic Agents; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta