Drug Metabolism Letters

Zhiyang Zhao
Amgen
Cambridge, MA
USA

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Heme Oxygenase-Derived Carbon Monoxide Restores Vascular Function in Type 1 Diabetes

Author(s): Luigi F. Rodella, Luca Vanella, Stephen J. Peterson, George Drummond, Rita Rezzani, John R. Falck, Nader G. Abraham.

Abstract:

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-α-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.

Keywords: Vascular repair, diabetes, thrombomodulin, adiponectin, inflammation, carbon monoxide

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Article Details

VOLUME: 2
ISSUE: 4
Year: 2008
Page: [290 - 300]
Pages: 11
DOI: 10.2174/187231208786734058
Price: $58