title: Diabetes impairs the vascular recruitment of normal stem cells by oxidant damage, reversed by increases in pAMPK, heme oxygenase-1, and adiponectin.
abstract: BACKGROUND
  Atherosclerosis progression is accelerated in diabetes mellitus (DM) by either direct endothelial damage or reduced availability and function of endothelial progenitor cells (EPCs). Both alterations are related to increased oxidant damage.
  
  
  OBJECTIVE
  We examined if DM specifically impairs vascular signaling, thereby reducing the recruitment of normal EPCs, and if increases in antioxidant levels by induction of heme oxygenase-1 (HO-1) can reverse this condition.
  
  
  METHODS
  Control and diabetic rats were treated with the HO-1 inducer cobalt protoporphyrin (CoPP) once a week for 3 weeks. Eight weeks after the development of diabetes, EPCs harvested from the aorta of syngenic inbred normal rats and labeled with technetium-99m-exametazime were infused via the femoral vein to estimate their blood clearance and aortic recruitment. Circulating endothelial cells (CECs) and the aortic expression of thrombomodulin (TM), CD31, and endothelial nitric oxide synthase (eNOS) were used to measure endothelial damage.
  
  
  RESULTS
  DM reduced blood clearance and aortic recruitment of EPCs. Both parameters were returned to control levels by CoPP treatment without affecting EPC kinetics in normal animals. These abnormalities of EPCs in DM were paralleled by reduced serum adiponectin levels, increased numbers of CECs, reduced endothelial expression of phosphorylated eNOS, and reduced levels of TM, CD31, and phosphorylated AMP-activated protein kinase (pAMPK). CoPP treatment restored all of these parameters to normal levels.
  
  
  CONCLUSIONS
  Type II DM and its related oxidant damage hamper the interaction between the vascular wall and normal EPCs by mechanisms that are, at least partially, reversed by the induction of HO-1 gene expression, adiponectin, and pAMPK levels.
authors.affiliation: Department of Internal Medicine, University of Genoa, S. Martino Hospital, Genoa, Italy. Sambuceti@unige.it
authors.forename: Gianmario
authors.initials: G
authors.lastname: Sambuceti
authors.forename: Silvia
authors.initials: S
authors.lastname: Morbelli
authors.forename: Luca
authors.initials: L
authors.lastname: Vanella
authors.forename: Claudia
authors.initials: C
authors.lastname: Kusmic
authors.forename: Cecilia
authors.initials: C
authors.lastname: Marini
authors.forename: Michela
authors.initials: M
authors.lastname: Massollo
authors.forename: Carla
authors.initials: C
authors.lastname: Augeri
authors.forename: Mirko
authors.initials: M
authors.lastname: Corselli
authors.forename: Chiara
authors.initials: C
authors.lastname: Ghersi
authors.forename: Barbara
authors.initials: B
authors.lastname: Chiavarina
authors.forename: Luigi F
authors.initials: LF
authors.lastname: Rodella
authors.forename: Antonio
authors.initials: A
authors.lastname: L'Abbate
authors.forename: George
authors.initials: G
authors.lastname: Drummond
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
authors.forename: Francesco
authors.initials: F
authors.lastname: Frassoni
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D052242:Adiponectin / Q000097:blood* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D042783:Endothelial Cells / Q000166:cytology*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011524:Protoporphyrins / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology*; D018180:Thrombomodulin / Q000378:metabolism
chemical_list: D052242:Adiponectin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011524:Protoporphyrins; D018180:Thrombomodulin; C007095:cobaltiprotoporphyrin; D052250:Nitric Oxide Synthase Type III; D051547:Heme Oxygenase-1; D055372:AMP-Activated Protein Kinases