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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\u2010endothelium interactions induced by hyperglycemia were examined by intravital microscopy. Intraperitoneal administration of the selective calpain inhibitor benzyloxycarbonyl\u2010leucyl\u2010leucinal (5 \u00b5mol\/L) prevented the up\u2010regulation of leukocyte\u2010endothelium interactions in response to 25 mmol\/L\n                    <jats:sc>d<\/jats:sc>\n                    \u2010glucose via a nitric oxide\u2010dependent mechanism. Furthermore, treatment of rats with\n                    <jats:sc>d<\/jats:sc>\n                    \u2010glucose significantly decreased basal endothelial NO release in mesenteric post\u2010capillary venules, a phenomenon prevented by inhibition of calpain activity. Immunoprecipitation studies revealed that glucose induces loss of NO via a calpain\u2010dependent 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\u2010inflammatory adhesion molecules ICAM\u20101 and VCAM\u20101 during hyperglycemia. These data demonstrate that calpains contribute to important inflammatory events during hyperglycemia and that pharmacological inhibition of calpain activity attenuates leukocyte\u2010endothelium interactions and preserves eNOS function.\n                  <\/jats:p>","DOI":"10.1096\/fj.02-1213fje","type":"journal-article","created":{"date-parts":[[2003,7,29]],"date-time":"2003-07-29T16:11:57Z","timestamp":1059495117000},"page":"1-19","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["A novel role for calpains in the endothelial dysfunction of hyperglycemia"],"prefix":"10.1096","volume":"17","author":[{"given":"Timothy J.","family":"Stalker","sequence":"first","affiliation":[{"name":"Department of Physiology Jefferson Medical College Thomas Jefferson University Philadelphia  Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher B.","family":"Skvarka","sequence":"additional","affiliation":[{"name":"Department of Physiology Jefferson Medical College Thomas Jefferson University Philadelphia  Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Scalia","sequence":"additional","affiliation":[{"name":"Department of Physiology Jefferson Medical College Thomas Jefferson University Philadelphia  Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2003,6,3]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.287.19.2570"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(96)00272-6"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.11.4651"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118074"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.2001.280.6.E848"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI656"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0703393"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3280721"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(93)90856-I"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.77.3.603"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00626.2001"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.99-0645com"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0701180"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.14.2.1459"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.52.36891"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.2000.278.6.L1204"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/33934"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212651200"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000016837.26733.BE"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a021280"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.1999.277.2.G463"},{"key":"e_1_2_6_23_1","first-page":"219","article-title":"Concurrent assessment of calpain and caspase-3 activity by means of western blots of protease-specific spectrin breakdown products","volume":"144","author":"Newcomb J. 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