Regulation of Heme Oxygenase-1 in cardiovascular diseases

Heme oxygenase-1 (HO-1) is the inducible rate-limiting enzyme in the oxidative degradation of heme, yielding equimolar amounts of carbon monoxide (CO), biliverdin, and ferrous iron. This reaction requires molecular oxygen, nicotinamide adenine dinucleotide phosphate, and the concerted action of cytochrome p450 reductase. This catabolic pathway is inhibited by various metalloporphyrins, including zinc and tin protoporphyin-IX. Biliverdin is metabolized to bilirubin by biliverdin reductase, and free iron is sequestered by ferritin and either excreted by cells or recycled for heme synthesis. HO-1 is a ubiquitously distributed, highly inducible enzyme. The expression of HO-1 is upregulated by numerous stimuli, including its substrate (heme), oxidants, heavy metals, cytokines, growth factors, gases, homocysteine, hormones, dietary antioxidants, radiation, hemodynamic forces, and by specific therapeutic agents. The control of HO-1 expression occurs primarily at the transcriptional level and is mediated by multiple signaling pathways and transcription factors. However, stress-activated transcription factors, such as nuclear factor E2-related factor-2 (Nrf2), activator protein-1, and nuclear factor-κB play predominant roles and mediate the potent induction of HO-1 by agents that cause cellular stress.

It is now well established that the induction of HO-1 provides a fundamental cellular defense mechanism against tissue injury. Compelling evidence indicates that HO-1 also protects against the development of cardiovascular disease. Genetic deficiency of HO-1 is associated with oxidative tissue damage, anemia, chronic inflammation, thrombosis, and increased susceptibility to atherosclerosis in both mice and humans, while overexpression of HO-1 improves vascular dysfunction in numerous animal models. In addition, functional polymorphisms in the promoter region of the HO-1 gene that are linked to impaired inducibility are associated with several cardiovascular pathologies. Further evidence for a beneficial role of HO-1 is provided by clinical studies, demonstrating that low serum concentrations of the heme metabolite, bilirubin, are correlated with an increased risk of coronary and peripheral artery disease.