Carbon monoxide and biliverdin prevent endothelial cell sloughing in rats with type I diabetes.
Hyperglycemia has been linked to increased oxidative stress, a resultant endothelial cell dysfunction, and, ultimately, apoptosis. Heme oxygenases (HO-1/HO-2) and the products of their activity, biliverdin/bilirubin and carbon monoxide (CO), play a physiological role in the vascular system. The effects of heme-mediated HO-1 induction, CO, and biliverdin on urinary 8-epi-isoprostane PGF(2alpha) and endothelial cell sloughing were examined in an animal model of streptozotocin (STZ)-induced diabetes. Hyperglycemia itself did not affect HO-1 and HO-2 protein levels, but caused a net decrease in HO activity. Weekly heme administration induced HO-1 protein, as demonstrated by immunohistochemistry and Western blot analyses. Administration of biliverdin or the CO donor, CORM-3, decreased urinary 8-epi-isoprostane PGF(2alpha), P < 0.5 compared to diabetes. Hyperglycemia increased endothelial cell sloughing; 8.2 +/- 0.8 cells/ml blood in control rats vs. 48 +/- 4.8 cells/ml blood in diabetic rats (P < 0.05). Heme administration significantly increased endothelial cell sloughing in diabetic rats (98 +/- 8.1 cells/ml blood, P < 0.0007) whereas biliverdin modestly decreased endothelial cell sloughing (26 +/- 3.5 cells/ml blood, P < 0.003). Administration of CORM-3 to diabetic rats resulted in a significant decrease in endothelial cell sloughing to 21.3 +/- 2.3 (P < 0.001). Administration of SnMP to CORM-3 diabetic rats only partially reversed the protective effects of CORM-3 on endothelial cell sloughing from 21.3 +/- 2.3 to 29 +/- 2.1 cells/ml, thus confirming a direct protective of CO, in addition to the ability of CORM-3 to induce HO-1 protein. These results demonstrate that exogenously administered CO or bilirubin can prevent endothelial cell sloughing in diabetic rats, likely via a decrease in oxidative stress, and thus represents a novel approach to prophylactic vascular protection in diabetes.
Rodella
Luigi
L
University of Texas Southwestern Medical Center, Dallas, USA.
Lamon
Brian D
BD
Rezzani
Rita
R
Sangras
Bhavani
B
Goodman
Alvin I
AI
Falck
John R
JR
Abraham
Nader G
NG
D000818:Animals; D001664:Biliverdine / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000494:pharmacology*; D002449:Cell Aggregation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000473:pathology*; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006418:Heme / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis; D051547:Heme Oxygenase-1 / Q000032:analysis; D009942:Organometallic Compounds / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats
D009942:Organometallic Compounds; D020011:Protective Agents; C476530:tricarbonylchloro(glycinato)ruthenium(II); C075750:8-epi-prostaglandin F2alpha; D006418:Heme; D002248:Carbon Monoxide; D015237:Dinoprost; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D001664:Biliverdine