Disease relevance of HMOX1

• The study population consisted of 1972 control subjects and 597 subjects with ischemic heart disease (myocardial infarction (MI) n = 393, HMOX1 n = 204) [1].
• The AA genotype of HMOX1 reduced the incidence of ischemic heart disease, possibly due to the high expression level of HMOX1 [1].
• Mechanism of Action of Sulforaphane: Inhibition of p38 Mitogen-Activated Protein Kinase Isoforms Contributing to the Induction of Antioxidant Response Element-Mediated Heme Oxygenase-1 in Human Hepatoma HepG2 Cells [2].
• By contrast, livers of idiopathic portal hypertension that are characterized by an increase in presinusoidal resistance displayed a significant decrease in the HO-1 expression in Kupffer cells, and its hepatocellular expression was not detectable [3].
• Upregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells [4].

Psychiatry related information on HMOX1

• Heme oxygenase-1 (HO), the heat shock/stress cognate of the heat shock protein 32 (HSP32) family of proteins, is postulated to be a component of cellular defense mechanisms against oxidative stress-mediated injury [5].
• Because SHR has been used as a model of vascular dementia and hippocampus is essential for spatial learning and memory, understanding of altered HO/CO and NOS/NO systems in the hippocampus of adult SHR may shed light on the pathogenic development of memory deficits associated with vascular dementia [6].
• We and others have previously reported that modulation of HO total activity may well have direct physiological implications in stroke and in Alzheimer's disease [7].
• Protection of human vascular smooth muscle cells from H2O2-induced apoptosis through functional codependence between HO-1 and AKT [8].
• Lymphocyte HO-1 mRNA levels were lower in the AD cohort relative to NEC (p < 0.001) and individuals with AACD, non-Alzheimer dementia, nondementing neurologic illness, and chronic medical conditions [9].

High impact information on HMOX1

• The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO) [10].
• Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications [10].
• This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress [10].
• IL-10-mediated protection against LPS-induced septic shock in mice was significantly attenuated by cotreatment with the HO inhibitor, zinc protoporphyrin [11].
• Here we report that HO-1 directly reduces vasoconstriction and inhibits cell proliferation during vascular injury [12].

Chemical compound and disease context of HMOX1

• The ability of synthetic metalloporphyrins to suppress heme oxygenase activity and bilirubin formation has recently become of considerable clinical and experimental interest for suppression of jaundice in humans, including neonatal hyperbilirubinemia [13].
• This study shows an antiapoptotic effect of heme oxygenase-1 in colon cancer cells which could be mediated by the formation of bilirubin and biliverdin [14].
• Higher levels of HO-1 may be a contributing factor for the undetectable levels of cytochrome P450 arachidonic acid metabolites, 20-HETE, in the adenocarcinoma [15].
• One of the consequences of impaired blood flow is glucose deprivation, which has been shown to be an inducer of HO-1 expression in HepG2 hepatoma cells [16].
• Baicalein inhibition of oxidative-stress-induced apoptosis via modulation of ERKs activation and induction of HO-1 gene expression in rat glioma cells C6 [17].

Biological context of HMOX1

• We sequenced HMOX1 and found a T(-413)A polymorphism in the promoter region [1].
• A (GT)(n) dinucleotide repeat in the 5'-flanking region of the human HO-1 gene (alias HMOX1) reduces HO-1 inducibility and shows length polymorphism, which is grouped into three classes: class S (<27 GT), class M (27-32 GT), and class L (>/=33 GT) alleles [18].
• We now show that there is an additional mechanism by which HO-1 inhibits apoptosis, namely by generating the gaseous molecule carbon monoxide (CO) [19].
• Heme oxygenase-1 (HO-1) protects cells from various insults including oxidative stress [20].
• Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene [20].

Anatomical context of HMOX1

• Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis [19].
• Interestingly, we observed that heme-induced influx of leukocytes was highly elevated after pharmacologic inhibition of HO activity [21].
• Surprisingly, we observed also that HO-1 is significantly expressed in the epithelium of both the mucosa and the skin of animals without wounds [21].
• In cirrhotic livers, which undergo portal hypertension through increases in intrasinusoidal resistance and regenerative changes in the parenchyma, HO-1 occurred in a majority of Kupffer cells and was also observed in hepatocytes [3].
• Induction of HO-1 by sulforaphane was attenuated by overexpression of mutant Nrf2 plasmid in HepG2 cells and totally abolished in Nrf2 knockout mouse embryonic keratinocytes and fibroblasts [2].

Associations of HMOX1 with chemical compounds

• Heme oxygenase (HO) catalyzes the conversion of heme to carbon monoxide, iron, and biliverdin, which is immediately reduced to bilirubin (BR) [22].
• The neuroprotective effects of PMA are prevented by the HO inhibitor tin protoporphyrin IX and in cultures from mice with deletion of HO2 gene [22].
• Using human HO-1 promoter reporter plasmids and ChIP assay, we have identified that sulforaphane transcriptionally activated the upstream ARE-rich enhancer region, located at -9.0 kb upstream human HO-1 promoter [2].
• Biliverdin reductase (BVR) reduces heme oxygenase (HO) activity product, biliverdin, to bilirubin [23].
• We show here that cadmium, a strong inducer of HO-1, activates the nuclear export of Bach1 [24].
• The KIT D816V-targeting drug PKC412 decreased the expression of Hsp32 as well as proliferation/survival in neoplastic MCs [25].

Physical interactions of HMOX1

• We propose a role for BVR in the signaling cascade for AP-1 complex activation necessary for HO-1 oxidative stress response [26].
• Activator protein-1 (AP-1) binding sites are located in the promoter region of HO-1 and MT genes and the effects of vitreous on c-fos activity were investigated [27].
• ALA stimulated translocation of the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) into the nucleus and binding to a human HO-1 antioxidant response element (ARE) by 30 minutes [28].
• A nuclear factor was shown both in untreated, and in the hIL-6-treated Hep3B cells that binds specifically to the IL-6-responsive element (IL6-RE) of the human HO gene [29].
• Transfection of PC12 cells with dominant-negative Nrf2 abolished the SIN-1-induced increase in Nrf2-ARE binding and subsequent upregulation of HO-1 expression, leading to enhanced cell death [30].

Enzymatic interactions of HMOX1

• Biliverdin IXalpha reductase (BVR) catalyzes reduction of the HO activity product, biliverdin, to bilirubin. hBVR is a serine/threonine kinase that contains a bZip domain [31].
• Human heme oxygenase-1 (hHO-1) catalyzes the NADPH-cytochrome P450 reductase-dependent oxidation of heme to biliverdin, CO, and free iron [32].
• Heme oxygenase catalyzes the NADPH, O2, and cytochrome P450 reductase dependent oxidation of heme to biliverdin and carbon monoxide [33].

Regulatory relationships of HMOX1

• CONCLUSIONS: HO-1 is involved in hemin-induced VEGF expression in HaCaT and may play a role in hypoxic regulation of this protein [34].
• Neither anti-VEGF nor anti-IL-8 antibodies influenced SNAP-induced HO-1 expression [35].
• HO-2 antisense ODN inhibited heme-induced HO activity by 21% [36].
• A dominant-negative Nrf2 inhibitor reduced ALA-induced HO-1 mRNA expression by 66% [28].
• Induction of heme oxygenase-1 inhibits monocyte chemoattractant protein-1 mRNA expression in U937 cells [37].

Other interactions of HMOX1

• In controls, approximately 50% of the total HO activity was from HO-1 as judged by the sensitivity to GTS-1, while the rest of activity was from other isozymes such as HO-2 [3].
• From a comparison of heavy metal responses of several human genes, it was noted that the heme oxygenase-1 (HO-1) gene is quite similar in the spectrum of metal response and induction kinetics to the heat shock protein 70 (HSP70) gene, suggesting a common regulatory mechanism shared by these genes [38].
• Lipopolysaccharide-induced heme oxygenase-1 expression in human monocytic cells is mediated via Nrf2 and protein kinase C [39].
• In hBVR-infected cells, levels of HO-1 mRNA and protein were increased [31].
• Oxidized phospholipids induce expression of human heme oxygenase-1 involving activation of cAMP-responsive element-binding protein [40].

Analytical, diagnostic and therapeutic context of HMOX1

• The peak activity at 1 h (4-5-fold) after treatment of 293A cells with 5 mum As preceded induction of HO-1 expression by 3 h [41].
• Unexpectedly, AEBSF induced endogenous gene expression and promoter activity of HO-1 in cell cultures of human and mouse monocytes [42].
• We sought evidence of expression of the two known isoforms of HO in normal human term placenta using reverse transcription polymerase chain reaction (RT-PCR), western blotting and immunohistochemistry [43].
• RT-PCR demonstrated the presence of messenger ribonucleic acid for HO-1 and HO-2 [43].
• In addition, administration of human HO-1 to rats in advance of ischemia/reperfusion injury considerably reduces tissue damage [44].

References