title: Inhibition of calpain reduces oxidative stress and attenuates endothelial dysfunction in diabetes.
abstract: OBJECTIVE
  The present study was to investigate the role of calpain in reactive oxygen species (ROS) production in endothelial cells and endothelium-dependent vascular dysfunction under experimental conditions of diabetes.
  
  
  RESULTS
  Exposure to high glucose activated calpain, induced apoptosis and reduced nitric oxide (NO) production without changing eNOS protein expression, its phosphorylation and dimers formation in primary human umbilical vein endothelial cells (HUVECs). These effects of high glucose correlated with intracellular ROS production and mitochondrial superoxide generation. Selectively scavenging mitochondrial superoxide increased NO production in high glucose-stimulated HUVECs. Inhibition of calpain using over-expression of calpastatin or pharmacological calpain inhibitor prevented high glucose-induced ROS production, mitochondrial superoxide generation and apoptosis, which were concurrent with an elevation of NO production in HUVECs. In mouse models of streptozotocin-induced type-1 diabetes and OVE26 type-1 diabetic mice, calpain activation correlated with an increase in ROS production and peroxynitrite formation in aortas. Transgenic over-expression of calpastatin reduced ROS production and peroxynitrite formation in diabetic mice. In parallel, diabetes-induced reduction of endothelium-dependent relaxation in aortic ring was reversed by over-expression of calpastatin in mouse models of diabetes. However, the protective effect of calpastatin on endothelium-dependent relaxation was abrogated by eNOS deletion in diabetic mice.
  
  
  CONCLUSIONS
  This study suggests that calpain may play a role in vascular endothelial cell ROS production and endothelium-dependent dysfunction in diabetes. Thus, calpain may be an important therapeutic target to overcome diabetes-induced vascular dysfunction.
authors.forename: Bainian
authors.initials: B
authors.lastname: Chen
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.forename: Rui
authors.initials: R
authors.lastname: Ni
authors.forename: Futian
authors.initials: F
authors.lastname: Tang
authors.forename: Limei
authors.initials: L
authors.lastname: Shan
authors.forename: Inga
authors.initials: I
authors.lastname: Cepinskas
authors.forename: Gediminas
authors.initials: G
authors.lastname: Cepinskas
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.affiliation: Institute for Cardiovascular Science of Soochow University, Suzhou, Jiangsu Province 215123, China. tqpeng@suda.edu.cn.
authors.forename: Tianqing
authors.initials: T
authors.lastname: Peng
mesh_terms: D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000502:physiology; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006023:Glycoproteins / Q000494:pharmacology / Q000627:therapeutic use; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D017382:Reactive Oxygen Species; C039304:calpain inhibitors; D002154:Calpain