Bilirubin: Striking Gold in Diabetic Vasculopathy?

Vascular complications are the primary cause of morbidity and mortality and a major contributor to health care costs in patients with diabetes (1). While the etiology of vascular disease is multifactorial, endothelial dysfunction characterized by a decrease in nitric oxide (NO) synthesis from endothelial NO synthase (eNOS) and blunted endothelium-dependent vasodilation is a seminal feature in diabetes-associated vascular disease. Given the dramatic increase in the incidence of diabetes worldwide, there is an urgent need for new therapies that targets this cellular defect in diabetes.Although long considered a toxic waste product of heme metabolism, the yellow pigment bilirubin is now recognized as an important vasoprotective molecule. Bilirubin is formed by the action of inducible heme oxygenase-1 (HO-1) or constitutively expressed HO-2, which degrades heme into biliverdin, carbon monoxide (CO), and iron (Fig. 1). Biliverdin is rapidly reduced to bilirubin by biliverdin reductase (BVR). Bilirubin is further processed in the liver, where it is conjugated with glucuronic acid by uridine diphosphate-glucuronosyltransferase A1A (UGT1A1) to a water-soluble form for elimination. While early work identified the potent antioxidant properties of bilirubin, more recent studies found that bilirubin elicits anti-inflammatory and antiapoptotic effects in endothelial cells and improves endothelium-dependent vasodilation in murine hypercholesterolemic blood vessels (2–5). Clinical studies also support a protective role, as serum bilirubin concentrations show an inverse relationship with risk for a constellation of cardiovascular disorders (6). Interestingly, serum bilirubin levels are lower …