Gene Transfection of H25A Mutant Heme Oxygenase-1 Protects Cells against Hydroperoxide-induced Cytotoxicity

Hori, Rio; Kashiba, Misato; Toma, Tomoko; Yachie, Akihiro; Goda, Nobuhito; Makino, Nobuya; Soejima, Akinori; Nagasawa, Toshihiko; Nakabayashi, Kimimasa; Suematsu, Makoto

doi:10.1074/jbc.m107749200

Cited by 105 publications

(81 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The data support our previous study, in which we showed that HO1 protects against NMDA-induced acute brain damage in mice (Ahmad et al, 2006). In addition, HO proteins likely have intrinsic cytoprotective properties (Hori et al, 2002;Kim and Doré, 2005). HO1 catalyzes the cleavage of heme (a pro-oxidant) to form iron (which can then increase ferritin levels), carbon monoxide (a vasodilator and anti-apoptotic agent), and biliverdin, which is rapidly reduced to bilirubin (an antioxidant) (Doré, 2002).…”

Section: Discussionsupporting

confidence: 92%

The Flavanol (−)-Epicatechin Prevents Stroke Damage through the Nrf2/HO1 Pathway

Shah

Ahmad

et al. 2010

J Cereb Blood Flow Metab

208

125

View full text Add to dashboard Cite

Epidemiologic studies have shown that foods rich in polyphenols, such as flavanols, can lower the risk of ischemic heart disease; however, the mechanism of protection has not been clearly established. In this study, we investigated whether epicatechin (EC), a flavanol in cocoa and tea, is protective against brain ischemic damage in mice. Wild-type mice pretreated orally with 5, 15, or 30 mg/kg EC before middle cerebral artery occlusion (MCAO) had significantly smaller brain infarcts and decreased neurologic deficit scores (NDS) than did the vehicle-treated group. Mice that were posttreated with 30 mg/kg of EC at 3.5 hours after MCAO also had significantly smaller brain infarcts and decreased NDS. Similarly, WT mice pretreated with 30 mg/kg of EC and subjected to N-methyl-D-aspartate (NMDA)-induced excitotoxicity had significantly smaller lesion volumes. Cell viability assays with neuronal cultures further confirmed that EC could protect neurons against oxidative insults. Interestingly, the EC-associated neuroprotection was mostly abolished in mice lacking the enzyme heme oxygenase 1 (HO1) or the transcriptional factor Nrf2, and in neurons derived from these knockout mice. These results suggest that EC exerts part of its beneficial effect through activation of Nrf2 and an increase in the neuroprotective HO1 enzyme.

show abstract

Section: Discussionsupporting

confidence: 92%

The Flavanol (−)-Epicatechin Prevents Stroke Damage through the Nrf2/HO1 Pathway

Shah

Ahmad

et al. 2010

J Cereb Blood Flow Metab

208

125

View full text Add to dashboard Cite

show abstract

“…Indeed, within a narrow therapeutic range, these catalytic by-products exert powerful antioxidant [15,31], antiinflammatory [32] and anti-apoptotic effects [33][34][35], leading to reduced infarct size [16,17,[36][37]. However, emerging evidence, suggests that HO-1 may also exert cytoprotective effects, independent of heme breakdown [38] by interacting with survival signaling pathways such as PI3K-Akt and p38. We reported recently that HO-1 functions co-dependently with Akt to confer protection from pro-oxidant-induced injury in human aortic smooth muscle cells [25].…”

Section: Discussionmentioning

confidence: 99%

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

Pachori

Smith

McDonald

et al. 2007

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Heme-oxygenase-1 (HO-1), a stress-inducible protein, is an important cytoprotective agent in various models of ischemia/reperfusion (I/R) injury. However, the role of downstream mediators involved in HO-1 induced cytoprotection is not clear. In the current study we investigated the role of biliverdin reductase, an enzyme involved in the conversion of HO-1 derived biliverdin into bilirubin and the PI3K/Akt pathway in mediating the cytoprotective effects of HO-1 against hypoxia and reoxygenation (H/R) injury in vitro and in vivo. H9c2 cardiomyocytes were transfected with a plasmid expressing HO-1 or LacZ and exposed to 24 hours of hypoxia followed by 12 hours of reoxygenation. At the end of reoxygenation, reactive oxygen species generation was determined using CM-H 2 DCFDA dye and apoptosis was assessed by TUNEL, caspase activity and Bad phosphorylation. p85 and Akt phosphorylation were determined using cell based ELISA and phospho-specific antibodies, respectively. HO-1 overexpression increased phosphorylation of the regulatory subunit of the PI3K (p85α) and downstream effector Akt in H9c2 cells, leading to decreased ROS and apoptosis. Furthermore, cardiac specific HO-1 expression increased basal phosphorylated Akt levels and decreased infarct size in response to LAD ligation and release induced I/R injury. Conversely, PI3K inhibition reversed the effects of HO-1 on Akt phosphorylation, cell death and infarct size. In addition, knockdown of biliverdin reductase (BVR) expression with siRNA attenuated HO-1 induced Akt phosphorylation and increased H/R-induced apoptosis of H9c2 cells. Co-immunoprecipitation revealed protein-protein interaction between BVR and the phosphorylated p85 subunit of the PI3 kinase. Taken together, these results suggest that the enzyme biliverdin reductase plays an important role in mediating cytoprotective effects of HO-1. This effect is mediated, at least in part, via activation of the PI3K/Akt pathway.

show abstract

“…Hori et al (39) transfected U937 macrophage-like cells with catalytically inactive HO-1, finding that these cells were still able to withstand peroxide challenge. Doré's laboratory demonstrated a protective effect of HO-2 during heme challenge both in vitro (40) and in vivo (41).…”

Section: Discussionmentioning

confidence: 99%

Non-heme Induction of Heme Oxygenase-1 Does Not Alter Cellular Iron Metabolism

Sheftel

Kim

Ponka

2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The catabolism of heme is carried out by members of the heme oxygenase (HO) family. The products of heme catabolism by HO-1 are ferrous iron, biliverdin (subsequently converted to bilirubin), and carbon monoxide. In addition to its function in the recycling of hemoglobin iron, this microsomal enzyme has been shown to protect cells in various stress models. Implicit in the reports of HO-1 cytoprotection to date are its effects on the cellular handling of heme/iron. However, the limited amount of uncommitted heme in non-erythroid cells brings to question the source of substrate for this enzyme in non-hemolytic circumstances. In the present study, HO-1 was induced by either sodium arsenite (reactive oxygen species producer) or hemin or overexpressed in the murine macrophage-like cell line, RAW 264.7. Both of the inducers elicited an increase in active HO-1; however, only hemin exposure caused an increase in the synthesis rate of the iron storage protein, ferritin. This effect of hemin was the direct result of the liberation of iron from heme by HO. Cells stably overexpressing HO-1, although protected from oxidative stress, did not display elevated basal ferritin synthesis. However, these cells did exhibit an increase in ferritin synthesis, compared with untransfected controls, in response to hemin treatment, suggesting that heme levels, and not HO-1, limit cellular heme catabolism. Our results suggest that the protection of cells from oxidative insult afforded by HO-1 is not due to the catabolism of significant amounts of cellular heme as thought previously.In the average adult, at equilibrium ϳ2 million red blood cells are being turned over every second. In a day, this process requires about 25 mg of iron (Fe) to be recycled from the hemoglobin of effete erythrocytes. Heme oxygenase 1 (HO-1) 2 is the enzyme responsible for catabolizing the heme from senescent red blood cells to release Fe, as well as equimolar amounts of carbon monoxide (CO) and biliverdin, for its eventual reuse in erythropoiesis. Another noninducible isoform of heme oxygenase with heme catabolic properties similar to HO-1, HO-2 is present in substantial levels primarily in the central nervous system and testes (1, 2). Although the heme-degrading function of HO has been known since the 1960s (3, 4), only recently has it been shown that heme oxygenases may be involved in cytoprotection against cellular stresses (for review see Camara and Soares (5), Abraham and Kappas (6), Otterbein et al. (7), and Ryter et al. (8)). This newer discovery of the potential of these enzymes as a tissue defense mechanism has spawned a flurry of studies by numerous groups who have shown by several different approaches that induction or overexpression of heme oxygenase 1 can protect tissues from various insults, including oxidative stress and immune system attack.The precise mechanism by which HO-1 mediates its protective function remains controversial. Breakdown of heme being the only known reaction catalyzed by the enzyme, extensive research has alleged that one or mo...

show abstract

Gene Transfection of H25A Mutant Heme Oxygenase-1 Protects Cells against Hydroperoxide-induced Cytotoxicity

Cited by 105 publications

References 26 publications

The Flavanol (−)-Epicatechin Prevents Stroke Damage through the Nrf2/HO1 Pathway

The Flavanol (−)-Epicatechin Prevents Stroke Damage through the Nrf2/HO1 Pathway

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

Non-heme Induction of Heme Oxygenase-1 Does Not Alter Cellular Iron Metabolism

Contact Info

Product

Resources

About