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

Luigi   F.   Rodella; Luca      Vanella; Stephen   J.   Peterson; George      Drummond; Rita      Rezzani; John   R.   Falck; Nader   G.   Abraham

doi:10.2174/187231208786734058

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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