Heme oxygenase-1: a novel therapeutic target for gastrointestinal diseases

Abstract

Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in the catabolism of heme, followed by production of biliverdin, free iron and carbon monoxide (CO). HO-1 is a stress-responsive protein induced by various oxidative agents. Recent studies demonstrate that the expression of HO-1 in response to different inflammatory mediators may contribute to the resolution of inflammation and has protective effects in several organs against oxidative injury. Although the mechanism underlying the anti-inflammatory actions of HO-1 remains poorly defined, both CO and biliverdin/bilirubin have been implicated in this response. In the gastrointestinal tract, HO-1 is shown to be transcriptionally induced in response to oxidative stress, preconditioning and acute inflammation. Recent studies suggest that the induction of HO-1 expression plays a critical protective role in intestinal damage models induced by ischemia-reperfusion, indomethacin, lipopolysaccharide-associated sepsis, trinitrobenzene sulfonic acid, and dextran sulfate sodium, indicating that activation of HO-1 may act as an endogenous defensive mechanism to reduce inflammation and tissue injury in the gastrointestinal tract. In addition, CO derived from HO-1 is shown to be involved in the regulation in gastro-intestinal motility. These in vitro and in vivo data suggest that HO-1 may be a novel therapeutic target in patients with gastrointestinal diseases.

Keywords: Bach1; Nrf2; bilirubin; carbon monoxide; heme oxygenase; indomethacin; ulcerative colitis.

Fig. 1

Model describing the regulation of ho-1 or other target genes by Bach1 and heme. Besides MafK, other Maf-related factors may also serve as partners for Bach1. Bach1 occupies MARE enhancers to repress transcription of ho-1 gene under normal conditions. An increase in heme levels alleviates Bach1-mediated repression through inhibition of its DNA-binding activity and subsequent nuclear export, making MAREs available for activating Maf complexes including Nrf2.

Fig. 2

(A) Effect of Bach1 deficiency on ulcer index in the intestinal mucosa treated with indomethacin. Data are expressed as means ± SEM of five to seven mice. (B) Macroscopic findings of the small intestine in mice treated with indomethacin. The administration of indomethacin provoked multiple erosions in the small intestine in wild type mice. On the other hand, in Bach1-deficient mice, the number and the severity of legions were clearly diminished.