Disease relevance of Hmox1

• After seven weeks of hypoxia, only HO-1(-/-) mice developed right ventricular infarcts with organized mural thrombi [1].
• Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice [1].
• RESULTS: CoPP strongly induced HO-1, resulting in the inhibition of cartilage erosion accompanied by extensive fibrosis in the joint [2].
• HO-1 mRNA is increased in mouse lung after 30 min of lung hilar clamping (ischemia) followed by 2-6 h of unclamping (reperfusion) compared with control mice [3].
• We investigated, by a combined in vivo and in vitro approach, the temporal changes of islet nitric oxide synthase (NOS)-derived nitric oxide (NO) and heme oxygenase (HO)-derived carbon monoxide (CO) production in relation to insulin and glucagon secretion during acute endotoxemia induced by lipopolysaccharide (LPS) in mice [4].
• HO-1-deficient mice suffered exaggerated lethality from polymicrobial sepsis [5].

Psychiatry related information on Hmox1

• Site of injury-directed induction of heme oxygenase-1 and -2 in experimental spinal cord injury: differential functions in neuronal defense mechanisms [6]?
• Neuronal overexpression of heme oxygenase-1 correlates with an attenuated exploratory behavior and causes an increase in neuronal NADPH diaphorase staining [7].
• These ocular dominance shifts occurred during a well-defined critical period, between P19 and P32 [8].
• Whole body images of HO-1 transcription patterns did, however; reveal increases in HO-1 transcription in Tg mice after treatment with other Mps, heme and cadmium chloride (CdCl(2)) [9].
• Importantly, both HO-1 and nontransgenic mice had normal sensorimotor function, and performed the same on a Y-maze alternation task, highlighting the specificity of memory deficit in the spatial navigation task [10].

High impact information on Hmox1

• Carbon monoxide (CO), one of the products of heme oxygenase action on heme, prevents arteriosclerotic lesions that occur following aorta transplantation; pre-exposure to 250 parts per million of CO for 1 hour before injury suppresses stenosis after carotid balloon injury in rats as well as in mice [11].
• Carbon monoxide (CO) can arrest cellular respiration, but paradoxically, it is synthesized endogenously by heme oxygenase type 1 (Ho-1) in response to ischemic stress [12].
• In the nervous system CO is formed by a subtype of heme oxygenase (HO) designated HO2 [13].
• A direct role for protective gene expression in endothelial cells was demonstrated by in vitro experiments in which induction of HO-1 or Bcl-xL suppressed alloantibody-stimulated endothelial activation [14].
• The anti-inflammatory properties of HO-1 are thought to rely on the ability of this enzyme to degrade heme and generate bilirubin, free iron and carbon monoxide [15].

Chemical compound and disease context of Hmox1

• Gliotoxin reduces the severity of trinitrobenzene sulfonic acid-induced colitis in mice: evidence of the connection between heme oxygenase-1 and the nuclear factor-kappaB pathway in vitro and in vivo [16].
• The induction of heme oxygenase-1 in renal adenocarcinoma cells was blocked by actinomycin D and cycloheximide and was abolished by the phosphatidylinositol 3-kinase inhibitor, LY294002, but not by the inactive analog LY303511 [17].
• Data demonstrated that Ad.HO-1 administration is as effective as the pharmacologic upregulation of the endogenous HO-1 gene expression by hemin to attenuate neutrophilic inflammations of the lung after aerosolized lipopolysaccharide (LPS) exposure [18].
• Here, the basal effect of heme oxygenase-1 was investigated in acute glutamatergic excitotoxicity to test the hypothesis that N-methyl-d-aspartate-induced acute toxicity in brain is attenuated by heme oxygenase-1 [19].
• Using a mouse scrapie model, we assessed oxidative stress in the brain at various stages of the disease progression and observed significantly increased concentration of lipid peroxidation markers, malondialdehyde and 4-hydroxyalkenals, and mRNA level of an oxidative stress response enzyme, heme oxygenase-1, at early preclinical stages of scrapie [20].

Biological context of Hmox1

• Using a genomic PAC clone, we demonstrate that the mouse Tom1 and Hmox1 genes are part of an as yet undescribed syntenic group between mouse chromosome 8C1 and human chromosome 22q13.1 [21].
• Compared with wild-type allografts, expression of inducible NO synthase (iNOS), which promotes the influx of cytoeffector leukocytes and airway graft rejection, was strikingly reduced by either enhanced expression of Hmox-1 or exogenous CO [22].
• Hmox-1/CO decreased nuclear factor (NF)-kappaB binding activity to the iNOS promoter region and iNOS expression [22].
• Hypoxia caused similar increases in right ventricular systolic pressure in wild-type and HO-1(-/-) mice [1].
• Lipid peroxidation and oxidative damage occurred in right ventricular cardiomyocytes in HO-1(-/-), but not wild-type, mice [1].

Anatomical context of Hmox1

• Similarly, the right ventricles were more dilated in HO-1(-/-) mice [1].
• Induction of heme oxygenase-1 expression in murine macrophages is essential for the anti-inflammatory effect of low dose 15-deoxy-Delta 12,14-prostaglandin J2 [23].
• Relevantly, ACTH and MTII incubation with primary peritoneal macrophages (Mphi) also induced HO-1 expression [24].
• Incubation of mouse embryonic fibroblasts with APG (5--40 microM) decreased hemin-induced HO-1 protein and mRNA expression [25].
• These roles for HO-1 and HO-2 were confirmed using detergent ablation of the epithelium to observe increased neurogenesis of ORNs after target disruption in HO null mice [26].

Associations of Hmox1 with chemical compounds

• In contrast, zinc protoporphyrin IX, a competitive inhibitor of Hmox, increased airway luminal occlusion [22].
• Heme oxygenase (HO) catalyzes the oxidation of heme to generate carbon monoxide (CO) and bilirubin [1].
• Treatment of cells with the protein synthesis inhibitor, cycloheximide, or the specific p38 MAP kinase inhibitor, SB203580, blocked the induction of HO-1 and suppression of LPS-induced I kappa B degradation mediated by 15d-PGJ2 [23].
• The heme oxygenase (HO) enzymes catalyze the rate-limiting step in the breakdown of heme to iron, carbon monoxide, and biliverdin [27].
• Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide [28].
• Preincubation with a cysteine protease inhibitor prevented nuclear entry of green fluorescent protein-labeled HO-1, demonstrating that protease-mediated C-terminal cleavage was also necessary for nuclear transport of HO-1 [29].
• Pharmacological induction of HO-1 and exposure to the end-product of HO-1 activity, carbon monoxide (CO), reduced ECM incidence in C57BL/6 mice to 10% and 0%, respectively [30].

Physical interactions of Hmox1

• Additional studies showed that EBS -93 binds Ets-2 and that mutation of the DNA binding domain of Ets-2 entirely prevented transactivation of HO-1 [31].
• Distal AP-1 binding sites mediate basal level enhancement and TPA induction of the mouse heme oxygenase-1 gene [32].

Enzymatic interactions of Hmox1

• Heme oxygenase catalyzes heme degradation and is an important component of the antioxidant defense [33].

Regulatory relationships of Hmox1

• MCP-1 is up-regulated in unstressed and stressed HO-1 knockout mice: Pathophysiologic correlates [34].
• Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts [35].
• The presence of the HO-1 inhibitor did not alter the 15d-PGJ(2)-induced inhibition of LPS-stimulated iNOS and TNFalpha protein levels, and led to only a partial reduction in the protection offered by 15d-PGJ(2) against LPS-induced nitrite production [36].
• HO-1 expression was significantly inhibited in the liver of TLR4 mutant mice [37].
• While the liver HO-1 expression in TNF KO mice was much lower than that in C57 mice following the same LPS treatment, IL-1beta KO had a slight influence on liver HO-1 expression following LPS treatment [37].

Other interactions of Hmox1

• The cytoprotection rendered by Stat4 disruption remains HO-1-dependent [38].
• However, use of more selective agonists (including melanotan (MTII)) indicated a predominant role for MC3-R in the induction of HO-1 expression and activity [24].
• CONCLUSION: In the absence of HO-1, expression of MCP-1 is significantly and consistently enhanced in unstressed and stressed conditions [34].
• However, L-NIL-mediated enzymatic inhibition of inducible NO-synthase (iNOS) at the wound site in vivo was not paralleled by decreased HO-1 levels [39].
• Using the tetracycline-regulated expression system, we show here that conditional overexpression of HO-1 prevents tumor necrosis factor-alpha-induced apoptosis in murine L929 fibroblasts [35].

Analytical, diagnostic and therapeutic context of Hmox1

• Induction of the enzyme responsible for the synthesis of CO, heme oxygenase (Hmox) 1, increased carboxyhemoglobin levels and suppressed lymphocytic bronchitis and airway luminal occlusion after transplantation [22].
• Western blot analysis revealed that the expression of the cytoprotective enzyme, heme oxygenase-1 (HO-1), was induced and coincident with the anti-inflammatory action of 15d-PGJ2 [23].
• The objective of the present study was to determine the consequences of HO-1 modulation in the murine collagen-induced arthritis (CIA) model [2].
• Besides a few keratinocytes of the hyperproliferative epithelium, immunohistochemistry revealed infiltrating macrophages as the predominant and major source of HO-1 at the wound site [39].
• Here we characterized the ontogeny of HO-1 and HO-2 expression in the developing mouse cortex by in vivo bioluminescence imaging, quantitative RT-PCR, and Western blot [40].

References