Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

Abstract

The heme oxygenase-1 (HO-1) enzyme system remains an attractive therapeutic target for the treatment of inflammatory conditions. HO-1, a cellular stress protein, serves a vital metabolic function as the rate-limiting step in the degradation of heme to generate carbon monoxide (CO), iron, and biliverdin-IXα (BV) which is converted to bilirubin-IXα (BR). HO-1 may function as a pleiotropic regulator of inflammatory signaling programs, through the generation of its biologically active end-products, namely CO and BV/BR. CO, when applied exogenously, can affect apoptotic, proliferative, and inflammatory cellular programs. Specifically, CO can modulate the production of pro- or anti-inflammatory cytokines and mediators. HO-1/CO may also have immunomodulatory effects with respect to regulating the functions of antigen-presenting cells, dendritic cells, and regulatory T-cells. Therapeutic strategies to modulate HO-1 in disease include the application of natural inducing compounds, as well as gene therapy approaches for the targeted genetic overexpression or knockdown of HO-1. Several compounds have been used therapeutically to inhibit HO activity, including competitive inhibitors of the metalloporphyrin series, or non-competitive isoform-selective derivatives of imidazole-dioxolanes. The end-products of HO activity, BV/BR and CO may be used therapeutically as pharmacological treatments. CO may be applied by inhalation, or through the use of CO releasing molecules (CORMs). This review will discuss HO-1 as a therapeutic target in diseases involving inflammation, including lung and vascular injury, sepsis, ischemia/reperfusion injury and transplant rejection.

Altered heme-mediated modulation of dendritic cell function in sickle cell alloimmunization

“…Its products, especially BV and CO, are thought to drive HO-1 immunomodulatory effects. [23][24][25][26][27] We therefore tested whether HO-1 could down-regulate CD83 through BV or CO. MoDCs were cultured in the presence of BV or the CO-release molecule CORM-3 28 before being matured with TLR agonists. Whereas heminmediated downregulation of CD83 was observed in both healthy donors (Online Supplementary Figure S4A) and nonalloimmunized SCD patients ( Figure 4C, left panel), HO-1 products had no effect in inhibiting CD83 expression ( Figure 4C, see CORM-3 or Biliverdin lanes).…”

Organic Nitrates in Heart Failure Revisited

“…HO-1-deficient mice reveal increased ROS formation in macrophages, whereas HO-1 induction reduced ROS levels and inflammatory cell chemotaxis. 4 Interestingly, the organic nitrate pentaerythritol tetranitrate (PETN), which is well tolerated and effective in patients with stable coronary artery disease, 5 is devoid of the development of nitrate tolerance at least in part by inducing HO-1 expression. 6 In this issue of Hypertension, Fracarollo et al 7 provide novel evidence that PETN can improve left ventricular remodeling and function in rats with ischemic heart failure.…”

Characterisation of the relationship between Heme-oxygenase-1 and adiponectin

“…These catalytic products modulate diverse features of cellular function and homeostasis in response to oxidative, inflammatory and metabolic stress [207,261,284]. In accordance with this, induction of HO-1 is typically promoted as an attractive therapeutic approach to reduce the incidence and severity of a variety of human diseases that include obesity and type 2 diabetes [195,262,284]. As such, strategies to induce HO-1 in humans are under investigation [206,207,263].…”

“…Heme oxygenase-1 (HO-1) is a stress-inducible protein that catalyses the oxidative degradation of heme to produce carbon monoxide (CO), iron and biliverdin/bilirubin [261,284]. These catalytic products modulate diverse features of cellular function and homeostasis in response to oxidative, inflammatory and metabolic stress [207,261,284].…”

“…HO-1 catalyses the oxidative degradation of heme to carbon monoxide (CO), iron and biliverdin/bilirubin [261,284], products that are known to modulate cellular function and homeostasis in response to a variety of inflammatory, oxidative and metabolic stresses [207,261,284]. Indeed, strategies to induce HO-1 in humans are under investigation [206,207,263] as this is generally considered an attractive therapeutic strategy in diseases including obesity and type 2 diabetes [195,262,284]. However, some lines of evidence suggest that HO-1 per se may not be involved [282] and may even play a negative role in the aetiology of obesity-associated inflammation and cardiometabolic complications [204].…”