Glucose-induced up-regulation of CD36 mediates oxidative stress and microvascular endothelial cell dysfunction

Aims/hypothesis: Hyperglycaemia-induced oxidative stress is implicated in the pathogenesis of chronic diabetic complications. Glucose-mediated oxidation of LDL may result in increased oxidative stress and vascular endothelial cell dysfunction via interaction with a cell surface scavenger receptor, CD36. In this study, we investigated the role of CD36 in cultured microvascular endothelial cells ( MVECs) and in the heart by using an animal model of chronic diabetes. Methods: Cultured MVECs were subjected to varying glucose concentrations and assayed for alteration in CD36 gene expression and protein levels. To assess for oxidised LDL ( ox-LDL) uptake, MVECs exposed to low and high glucose were treated with ox-LDL ( 80 mu g/ml), a ligand for CD36. Haem oxygenase-1 ( HO-1) and endothelin-1 ( ET-1) induction, as well as oxidative stress were determined. The role of glucose-induced CD36 alteration in ox-LDL uptake was also assayed following post-transcriptional CD36 gene silencing. For in vivo studies, CD36 mRNA and oxidative DNA and protein damage were measured in heart tissues of 1-month-old diabetic Sprague-Dawley rats. Results: We found that glucose increased CD36 mRNA and protein levels in MVECs. High levels of glucose also augmented ox-LDL uptake, in association with increasing HO-1 and ET-1 mRNA levels. CD36 gene silencing prevented glucose-induced CD36 alteration, reduced ox-LDL uptake, and prevented HO-1 and ET-1 up-regulation. Similar to in vitro studies, diabetic heart tissues exhibited increased CD36 mRNA levels and increased oxidative DNA and protein damage. Conclusions/interpretation: Our results provide evidence that up-regulation of CD36 may have a role in increasing oxidative stress in MVECs and the heart in chronic diabetes.