Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

Abstract

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

Heme Oxygenase 1 in Vertebrates: Friend and Foe

“…The importance of HO-1 for vertebrates' physiology is demonstrated by hmox-1 deficient mice that mimic several abnormal features observed in 9 case reports of HO-1 deficient/mutant human patients [35]. In general, HO-1 deficiency is associated with reduced life span, asplenia/ spleen abnormalities, hepatomegaly, proteinuria, hemolytic anemia with paradoxical normo-or hypobilirubinemia, abnormal liver iron deposition, elevated thrombomodulin and von Willebrand factor on plasma, deleterious inflammation, and elevated levels of serum heme concentrations.…”

The Role of HO-1 and Its Crosstalk with Oxidative Stress in Cancer Cell Survival

“…Several in vivo studies with HO-1-deficiency have demonstrated a cytoprotective effect of HO-1 in human diseases including systemic inflammation, hemolysis, nephritis, asplenia, nephropathy, and vascular endothelial injury [ 9 , 10 ]. Results from clinical studies further confirmed that HO-1 protects cells by diminishing oxidative stress and inflammation, and maintaining mitochondrial integrity, thereby promoting cell survival [ 11 ]. Due to the manner in regulation of iron metabolism [ 12 ], HO-1 also play a role in mediating ferroptosis, a newly identified iron-dependent cell death [ 13 , 14 , 15 , 16 ].…”

Exosomes and Micro-RNAs in Aging Process

“…Mi-RNA-204/mi-RNA-211 attenuated vascular calcification and induced aging in a paracrine way through BMP2 [177]. On the contrary, bone marrow stromal cells expressing mi-RNA-183-5p showed a decreased ability of Hmox1 to protect from oxidative stress and excessive inflammatory reactions resulting in senescence and a reduced osteogenic differentiation [185].…”