The Multifunctional Role and Therapeutic Potential of HO-1 in the Vascular Endothelium

Significance: Heme oxygenases (HO-1 and HO-2) catalyze the degradation of the pro-oxidant heme into carbon monoxide (CO), iron, and biliverdin, which is subsequently converted to bilirubin. In the vasculature, particular interest has focused on antioxidant and anti-inflammatory properties of the inducible HO-1 isoform in the vascular endothelium. This review will present evidence that illustrates the potential therapeutic significance of HO-1 and its products, with special emphasis placed on their beneficial effects on the endothelium in vascular diseases. Recent Advances: The understanding of the molecular basis for the regulation and functions of HO-1 has led to the identification of a variety of drugs that increase HO-1 activity in the vascular endothelium. Moreover, therapeutic delivery of HO-1 products CO, biliverdin, and bilirubin has been shown to have favorable effects, notably on endothelial cells and in animal models of vascular disease. Critical Issues: To date, mechanistic data identifying the downstream target genes utilized by HO-1 and its products to exert their actions remain relatively sparse. Likewise, studies in man to investigate the efficacy of therapeutics known to induce HO-1 or the consequences of the tissue-specific delivery of CO or biliverdin/bilirubin are rarely performed. Future Directions: Based on the promising in vivo data from animal models, clinical trials to explore the safety and efficacy of the therapeutic induction of HO-1 and the delivery of its products should now be pursued further, targeting, for example, patients with severe atherosclerotic disease, ischemic limbs, restenosis injury, or at high risk of organ rejection. Antioxid. Redox Signal. 20, 1789-1809.