Diabetes impairs the vascular recruitment of normal stem cells by oxidant damage, reversed by increases in pAMPK, heme oxygenase-1, and adiponectin.
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.
Sambuceti
Gianmario
G
Department of Internal Medicine, University of Genoa, S. Martino Hospital, Genoa, Italy. Sambuceti@unige.it
Morbelli
Silvia
S
Vanella
Luca
L
Kusmic
Claudia
C
Marini
Cecilia
C
Massollo
Michela
M
Augeri
Carla
C
Corselli
Mirko
M
Ghersi
Chiara
C
Chiavarina
Barbara
B
Rodella
Luigi F
LF
L'Abbate
Antonio
A
Drummond
George
G
Abraham
Nader G
NG
Frassoni
Francesco
F
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
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