Protein kinase C-beta inhibition and diabetic microangiopathy: effects on endothelial permeability responses in vitro.
Protein kinase C (PKC)-beta and other PKC isozymes have been implicated in the loss of endothelial barrier function in diabetic microangiopathy. The effects of a PKC-beta-specific inhibitor, LY379196, on hyperpermeability responses to high-glucose, angiotensin II, alpha-thrombin and endothelin-1 were evaluated using an in vitro model of human pulmonary artery endothelial cell monolayers. LY379196 attenuated the increase in transendothelial albumin flux induced by glucose 40 mM (e.g. 411+/-160% [high-glucose] vs. 167+37% [high-glucose+LY379196], P<0.001) and angiotensin II 10 microM (e.g. 121+/-12% vs. 246+/-35%, P<0.01); endothelin-1 had no significant effect on monolayer permeability. LY379196 had no significant effect on the marked hyperpermeability response to alpha-thrombin 1 microM. Thus, two major pathways involved in vascular leakage in diabetic microangiopathy are amenable to therapeutic blockade by PKC-beta inhibition.
Idris
Iskandar
I
Centre for Integrated Systems Biology and Medicine, School of Medical and Surgical Sciences, University of Nottingham, Nottingham, UK.
Gray
Samuel
S
Donnelly
Richard
R
D000804:Angiotensin II / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D008698:Mesylates / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064546:Protein Kinase C beta; D011758:Pyrroles / Q000494:pharmacology
C434605:5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate; D004791:Enzyme Inhibitors; D008698:Mesylates; D011758:Pyrroles; D000804:Angiotensin II; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D005947:Glucose