title: Tissue-specific up-regulation of arginase I and II induced by p38 MAPK mediates endothelial dysfunction in type 1 diabetes mellitus.
abstract: OBJECTIVE
  Emerging evidence suggests a selective up-regulation of arginase I in diabetes causing coronary artery disease; however, the mechanisms behind this up-regulation are still unknown. Activated p38 MAPK has been reported to increase arginase II in various cardiovascular diseases. We therefore tested the role of p38 MAPK in the regulation of arginase I and II expression and its effect on endothelial dysfunction in diabetes mellitus.
  
  
  METHODS
  Endothelial function was determined in septal coronary (SCA), left anterior descending coronary (LAD) and mesenteric (MA) arteries from healthy and streptozotocin-induced diabetic Wistar rats by wire myographs. Arginase activity and protein levels of arginase I, II, phospho-p38 MAPK and phospho-endothelial NOS (eNOS) (Ser(1177) ) were determined in these arteries from diabetic and healthy rats treated with a p38 MAPK inhibitor in vivo.
  
  
  RESULTS
  Diabetic SCA and MA displayed impaired endothelium-dependent relaxation, which was prevented by arginase and p38 MAPK inhibition while LAD relaxation was not affected. Arginase I, phospho-p38 MAPK and eNOS protein expression was increased in diabetic coronary arteries. In diabetic MA, however, increased expression of arginase II and phospho-p38 MAPK, increased arginase activity and decreased expression of eNOS were observed. All these effects were reversed by p38 MAPK inhibition.
  
  
  CONCLUSIONS
  Diabetes-induced activation of p38 MAPK causes endothelial dysfunction via selective up-regulation of arginase I expression in coronary arteries and arginase II expression in MA. Therefore, regional differences appear to exist in the arginase isoforms contributing to endothelial dysfunction in type 1 diabetes mellitus.
authors.affiliation: Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Pernow
authors.affiliation: Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Kiss
authors.affiliation: Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Y
authors.initials: Y
authors.lastname: Tratsiakovich
authors.affiliation: Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.|Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Climent
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism*; D003331:Coronary Vessels / Q000378:metabolism / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017208:Rats, Wistar; D015854:Up-Regulation; D014664:Vasodilation / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases; C113162:Arg2 protein, rat; D001119:Arginase; C542908:arginase I, rat