Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat.

Nath, Karl A.; Balla, György; Vercellotti, Gregory M.; Balla, József; Jacob, Harry S.; Levitt, Michael D.; Rosenberg, Mark E.

doi:10.1172/jci115847

Cited by 655 publications

(587 citation statements)

References 22 publications

(32 reference statements)

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“…Although plasma hemoglobin and heme-binding proteins such as haptoglobin, hemopexin, and albumin are able to prevent the liberation and toxicity of heme, excessive release of hemoprotein will presumably saturate these buffering systems, allowing heme to enter endothelial cells. This is the case in rhabdomyolysis, a disease in which Nath et al (30) have demonstrated that HO-1 induction provides protection to tissues presumably through the subsequent increases in Ft and bilirubin. Ischemia-reperfusion injury will also bring about significant intravascular hemolysis (31,32), again supplying substrate for HO.…”

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

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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...

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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

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“…Haem oxygenase is the ratelimiting enzyme in haem degradation to CO, iron and biliverdin, the latter being converted into bilirubin by biliverdin reductase [3]. The proposed antioxidant role for HO-1 is based on some crucial experimental observations : (i) HO-1 gene expression is extremely sensitive to up-regulation by oxidative stress in a variety of mammalian tissues [2,[4][5][6] ; (ii) induction of HO-1 protein or transfection of cells with the HO-1 gene protect tissues against oxidant-mediated injury [7][8][9][10] ; and (iii) HO-1 knockout mice exhibit reduced stress defences when exposed to oxidative challenge [11]. Since biliverdin and bilirubin have been shown to possess potent antioxidant properties [12] and upregulation of HO-1 is usually accompanied by increased levels of ferritin, a protein which sequesters intracellular catalytic iron [13], HO-1 appears to be an excellent candidate for cytoprotection.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress

Clark

Foresti

Green

et al. 2000

Biochemical Journal

217

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The inducible isoform of haem oxygenase (HO-1) has been proposed as an effective system to counteract oxidant-induced cell injury. In several circumstances, this cytoprotective effect has been attributed to increased generation of the antioxidant bilirubin during haem degradation by HO-1. However, a direct implication for HO-1-derived bilirubin in protection against oxidative stress remains to be established. In the present study, we examined the dynamics of HO-1 expression and bilirubin production after stimulation of vascular smooth-muscle cells with hemin, a potent inducer of the HO-1 gene. We found that hemin-mediated increase in HO-1 protein expression and haem oxygenase activity is associated with augmented bilirubin levels. The majority of bilirubin production occurred early after exposure of cells to hemin. Hemin pre-treatment also resulted in high resistance to cell injury caused by an oxidant-generating system. Interestingly, this protective effect was manifest only when cells were actively producing bilirubin as a consequence of increased haem availability and utilization by HO-1. Tin protoporphyrin IX, an inhibitor of haem oxygenase activity, significantly reduced bilirubin generation and reversed cellular protection afforded by hemin treatment. Furthermore, addition of bilirubin to the culture medium markedly reduced the cytotoxicity produced by oxidants. Our findings provide direct evidence that bilirubin generated after up-regulation of the HO-1 pathway is cytoprotective against oxidative stress.

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“…Experiments with HO-2 knock-out mice reveal the accumulation of iron in the lung after hyperoxic exposure ; this occurs without the induction of ferritin [24]. Indeed, the protective effects attributed to HO might actually reside in the induction of ferritin, rather than in HO-1 itself, as was seen in a rodent rhabdomyolysis model [12]. Similar findings have been confirmed in endothelial cells, where it was the induction of ferritin and not HO up-regulation that protected cells against the toxicity of H # O # [23].…”

Section: Figure 5 Hne Formationmentioning

confidence: 97%

“…Test incubations contained 100 µl of Hb (0.1 mg\ml, final concentration) in place of buffer. Hb has been used previously in studies with HO [12,20]. It might not be the ultimate form of haem utilized by the enzyme in i o but it is definable, readily soluble and biologically relevant.…”

Section: Conditions Of Incubationmentioning

confidence: 99%

“…HO-1 is a stress protein known as heat shock protein 32. Its transcription can be induced by a whole array of stresses, including endotoxin [4][5][6][7], transition-metal ions [8], haem, haemin, Hb and other haem proteins [9][10][11][12], and oxidative stress [13][14][15]. Indeed, it has been suggested that HO-1 induction might represent a generalized response to oxidative stress [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Haem oxygenase shows pro-oxidant activity in microsomal and cellular systems: implications for the release of low-molecular-mass iron

Lamb

Quinlan

Mumby

et al. 1999

Biochemical Journal

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Haem oxygenase-1 (HO-1) is a highly inducible stress protein that removes haem from cells with the release of biliverdin, carbon monoxide and low-molecular-mass iron (LMrFe). Several antioxidant functions have been ascribed to HO; its induction is considered to be a protective event. However, LMrFe produced during haem catabolism might elicit a pro-oxidant response, with deleterious consequences. We therefore investigated the delicate balance between pro-oxidant and antioxidant events with the use of a microsomal lipid peroxidation (LPO) system. By using microsomal-bound HO in an NADPH-dependent LPO system, we assessed the pro-oxidant nature of the released LMrFe and the antioxidant effect of the released bilirubin. Hb, a biologically relevant substrate for HO, was included with the microsomes to supplement the source of haem iron and to promote LPO. We found significant increases in microsomal LPO, by using the thiobarbituric acid (TBA) test, after incubation with Hb. This Hb-stimulated peroxidation was inhibited by HO inhibitors and by iron chelators, suggesting a HO-driven, iron-dependent mechanism. GLC-MS was employed to measure the specific LPO product 4-hydroxy-2-nonenal and to confirm our TBA test results. A HO inhibitor attenuated an increase in intracellular LMrFe that occurred after treatment of rat pulmonary artery smooth-muscle cells with Hb. Additionally, exogenously added bilirubin at an equimolar concentration to the LMrFe present in both microsomal and liposomal systems was unable to prevent the pro-oxidant effect of the iron. Under certain circumstances HO can act as a pro-oxidant and seems to have a role in stimulating microsomal LPO.

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Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat.

Cited by 655 publications

References 22 publications

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

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

Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress

Haem oxygenase shows pro-oxidant activity in microsomal and cellular systems: implications for the release of low-molecular-mass iron

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