Heme oxygenase-derived carbon monoxide restores vascular function in type 1 diabetes.
Increased heme oxygenase-1 (HO-1) expression improves vascular function by decreasing superoxide and increasing antioxidant levels. We therefore examined if HO-1 induction increased serum adiponectin levels and ameliorated vascular dysfunction in Type 1 diabetes. Administration of either carbon monoxide (CORM-3) or the HO-1 inducers, Resveratrol, and cobalt protoporphyrin (CoPP), increased serum levels of adiponectin (high molecular weight) in diabetic (streptozotocin; STZ-induced) Sprague Dawley rats. Resveratrol and CoPP administration increased HO-1 protein expression and HO activity in the aorta and significantly (p<0.05) increased serum adiponectin levels, compared to untreated diabetic rats. The results obtained with the CO releasing molecule, CORM-3, indicate a direct involvement of CO leading to increased levels of adiponectin. The increase in adiponectin was associated with a significant decrease in circulating endothelial cells (CEC) (p<0.002), decreased EC fragmentations and a significant increase in thrombomodulin (TM) and CD31(+) cells (p<0.05). Increased adiponectin levels were associated with a decrease in TNF-alpha-induced ICAM-1 and VCAM-1 and caspase 3 activity in endothelial cells while phosphorylation of eNOS at Ser-1179 increased. The adiponectin mediated increase in peNOS and pAKT was prevented by the phosphatidylinositol-3 kinase inhibitor, LY294002. In conclusion, there appears to be a temporal HO-1-adiponectin relationship that has a key role in vascular protection in Type 1 diabetes via a mechanism that involves increased levels of carbon monoxide.
Department of Biomedical Science, University of Brescia, Italy.
Luigi F
LF
Rodella
Luca
L
Vanella
Stephen J
SJ
Peterson
George
G
Drummond
Rita
R
Rezzani
John R
JR
Falck
Nader G
NG
Abraham
D052242:Adiponectin / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000503:physiopathology*; D042783:Endothelial Cells / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008297:Male; D009942:Organometallic Compounds / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D013311:Streptozocin
D052242:Adiponectin; D009942:Organometallic Compounds; D011524:Protoporphyrins; D013267:Stilbenes; C476530:tricarbonylchloro(glycinato)ruthenium(II); D013311:Streptozocin; C007095:cobaltiprotoporphyrin; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D000077185:Resveratrol