A novel role for calpains in the endothelial dysfunction of hyperglycemia.
Recent studies have reported that the activity of the calcium-dependent protease calpain is increased in acute inflammatory processes of the cardiovascular system. Because diabetes is associated with vascular inflammation, we hypothesized that increased calpain activity in response to hyperglycemia may play a role in diabetic cardiovascular disease. The effects of calpain inhibition on leukocyte-endothelium interactions induced by hyperglycemia were examined by intravital microscopy. Intraperitoneal administration of the selective calpain inhibitor benzyloxycarbonyl-leucyl-leucinal (5 micromol/L) prevented the up-regulation of leukocyte-endothelium interactions in response to 25 mmol/L D-glucose via a nitric oxide-dependent mechanism. Furthermore, treatment of rats with D-glucose significantly decreased basal endothelial NO release in mesenteric post-capillary venules, a phenomenon prevented by inhibition of calpain activity. Immunoprecipitation studies revealed that glucose induces loss of NO via a calpain-dependent decrease in the association of hsp90 with endothelial nitric oxide synthase. In addition, inhibition of calpain activity decreased endothelial cell surface expression of the pro-inflammatory adhesion molecules ICAM-1 and VCAM-1 during hyperglycemia. These data demonstrate that calpains contribute to important inflammatory events during hyperglycemia and that pharmacological inhibition of calpain activity attenuates leukocyte-endothelium interactions and preserves eNOS function.
Stalker
Timothy J
TJ
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107-6799, USA. Rosario.Scalia@mail.tju.edu
Skvarka
Christopher B
CB
Scalia
Rosario
R
D000818:Animals; D002154:Calpain / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D008643:Mesentery / Q000201:enzymology; D008954:Models, Biological; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017207:Rats, Sprague-Dawley
D015815:Cell Adhesion Molecules; D018841:HSP90 Heat-Shock Proteins; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D002154:Calpain; D005947:Glucose