title: Mechanisms of amelioration of glucose-induced endothelial dysfunction following inhibition of protein kinase C in vivo.
abstract: Inhibition of protein kinase C (PKC) activity has been shown to improve the endothelial dysfunction associated with hyperglycemia and diabetes. The mechanisms by which inhibition of PKC activity ameliorates endothelial dysfunction in diabetes are not well understood. We investigated the relationship between PKC inhibition and leukocyte-endothelium interaction in the microcirculation of the rat mesentery exposed to 25 mmol/l D-glucose for 12 h. D-Glucose significantly increased leukocyte rolling and adherence in mesenteric postcapillary venules. This proinflammatory action of D-glucose was inhibited by superfusion of the mesentery with 30 nmol/l bisindolylmaleimide-I, a potent, selective PKC inhibitor (P < 0.01 vs. glucose alone after 90 min of superfusion). Immunohistochemical localization of the cell adhesion molecules P-selectin and intercellular adhesion molecule (ICAM)-1 on the endothelial cell surface was increased by 25 mmol/l D-glucose (P < 0.001 vs. control tissue from rats injected with saline), which was significantly reduced by bisindolylmaleimide-I (P < 0.001 vs. glucose alone). In addition, we studied adhesion of isolated neutrophils to rat superior mesenteric artery (SMA) vascular segments stimulated with 25 mmol/l D-glucose for 4 h in vitro. Pretreatment of the SMA vascular segments with either superoxide dismutase enzyme (100 units/ml) or bisindolylmaleimide-I (30 nmol/l) equally inhibited the increased neutrophil adherence to SMA endothelium in response to glucose. These data demonstrate that inhibition of PKC activity reduces leukocyte-endothelium interactions by suppressing surface expression of endothelial cell adhesion molecules in response to increased oxidative stress. These results provide a novel mechanism by which inhibition of PKC activity improves endothelial cell function in hyperglycemia and diabetes.
authors.affiliation: Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-6799, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Booth
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Stalker
authors.forename: Allan M
authors.initials: AM
authors.lastname: Lefer
authors.forename: Rosario
authors.initials: R
authors.lastname: Scalia
mesh_terms: D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D003925:Diabetic Angiopathies / Q000378:metabolism; D004730:Endothelium, Vascular / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D019007:P-Selectin / Q000032:analysis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D019007:P-Selectin; C115989:bisindolylmaleimide V; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D011493:Protein Kinase C; D005947:Glucose; C070515:bisindolylmaleimide I