Does carbon monoxide have a physiological function?

Marks, Gerald S.; Brien, James F.; Nakatsu, Kanji; McLaughlin, Brian E.

doi:10.1016/0165-6147(91)90544-3

Cited by 404 publications

(198 citation statements)

References 19 publications

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“…A strategic approach to the treatment of neonatal jaundice would be to selectively inhibit HO-1 activity induced by hemolysis in order to prevent excessive bilirubin formation. However, it would be desirable, if not important, to maintain differentially the activity of the 'housekeeping' HO-2 isoenzyme, which may have a role in the production of CO necessary for physiological functioning, 25 and of bilirubin for the maintenance of tissue antioxidant levels. 26,27 Alternatively, the selective inhibition of HO-2 could allow the study of the function of HO-2, as well as the physiological roles for CO and bilirubin.…”

Section: Introductionmentioning

confidence: 99%

In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins

et al. 2011

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Objective: Neonatal jaundice results from an increased bilirubin production and decreased hepatic bilirubin conjugation and excretion. Severe hyperbilirubinemia is currently treated with phototherapy or exchange transfusion; however, its prevention by inhibiting bilirubin formation is a more logical strategy. Heme oxygenase (HO), with inducible (HO-1) and constitutive (HO-2) isoenzymes, is the rate-limiting enzyme in heme catabolism, producing equimolar amounts of bilirubin and carbon monoxide (CO). Metalloporphyrins (Mps) are heme derivatives that competitively inhibit HO and thereby suppress hyperbilirubinemia. No systematic studies have been reported evaluating whether the HO isoenzymes are inhibited differentially by various Mps. Identification of Mps that selectively inhibit the inducible HO-1 without affecting the 'housekeeping' HO-2 isoenzyme might be desirable in the clinical setting of hemolytic disease, in which the Hmox1 gene is greatly induced. Although bilirubin production is due to the activity of both HO-1 and HO-2, the inhibition of HO-1 with a relative sparing of HO-2 activity might provide the most selective approach for the treatment of hemolytic disease.Study Design: We determined for the deutero-, proto-, meso-and bisglycol porphyrins with zinc, tin and chromium as central atoms, respectively, the concentration needed for 50% inhibition (I 50 ) of HO-1 and HO-2 activities in rat spleen and brain tissue.Result: For a given Mp, HO-1 activity was less inhibited than that of HO-2. The order of inhibitor potency of each Mp was nearly identical for both isoenzymes. Tin mesoporphyrin was the most potent inhibitor for both isoenzymes. HO-2 selectivity was greatest for tin protoporphyrin. Conversely, the Zn compounds were least inhibitory toward HO-2. No Mp preferentially inhibited HO-1. Conclusion:Mps that produce a less inhibitory effect on HO-2, while limiting the response of the inducible HO-1, such as ZnPP, may be a useful clinical tool.

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Section: Introductionmentioning

confidence: 99%

In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins

et al. 2011

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“…In addition, bilirubin possesses antioxidant activity (10). Carbon monoxide, which is chemically very similar to nitrogen monoxide (NO) (11), can bind to the heme groups in various proteins to modulate their function. By this property, it has been shown that CO may initiate intracellular signaling cascades related to cell survival, mimicking the effects of HO-1 induction (2,5,12,13).…”

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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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“…CO is a gas molecule that shares some of the properties of NO, inasmuch as CO binds to the heme moiety of cytosolic guanylyl cyclase to produce cGMP (10). Two distinct forms of heme oxygenase have been identified (9): HO-1 (an inducible isozyme) and HO-2 (a non-inducible isozyme).…”

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confidence: 99%

Induction of Heme Oxygenase-1 Expression in Vascular Smooth Muscle Cells

Yet

Pellacani

Patterson

et al. 1997

Journal of Biological Chemistry

182

153

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Endotoxic shock is a life-threatening consequence of severe Gram-negative infection characterized by vascular smooth muscle cell relaxation and severe hypotension. The production of nitric oxide (NO), through the inducible NO synthase pathway, has been implicated as a major contributor in this process. We now demonstrate that heme oxygenase (HO), an enzyme that generates carbon monoxide (CO) in the course of heme metabolism, may also be involved in the hemodynamic compromise of endotoxic shock. Inducible HO (HO-1) mRNA levels are dramatically increased in aortic tissue from rats receiving endotoxin, and this increase in vascular HO-1 message is associated with an 8.9-fold increase in HO enzyme activity in vivo. Immunocytochemical staining localizes an increase in HO-1 protein within smooth muscle cells of both large (aorta) and small (arterioles) blood vessels. Furthermore, zinc protoporphyrin IX, an inhibitor of HO activity, abrogates endotoxin-induced hypotension in rats. Studies performed in rat vascular smooth muscle cells in vitro show that the induction of HO-1 mRNA is regulated at the level of gene transcription, and this induction is independent of NO production. Taken together, these studies suggest that the up-regulation of HO-1, and the subsequent production of CO, contributes to the reduction in vascular tone during endotoxic shock.Endotoxemia leading to shock is a detrimental consequence of severe Gram-negative bacterial infection. Endotoxic shock is initiated by the release of bacterial cell wall-derived lipopolysaccharide (LPS) 1 and the subsequent production of cytokines and vasoactive mediators that result in vascular smooth muscle cell relaxation and hypotension (1, 2). One of the most important cytokines in the cascade of events leading to LPSinduced hypotension is interleukin (IL)-1␤ (1, 3). We have demonstrated previously that IL-1␤ stimulates the inducible isoform of nitric oxide synthase (NOS) and increases the production of NO in vascular smooth muscle cells (4). NO is a labile, free radical gas that acts as a potent vasodilator (5, 6). The importance of NO in the pathogenesis of endotoxic shock has been emphasized by recent studies demonstrating that mice carrying a disrupted inducible NOS gene have an attenuated hypotensive-response to LPS (7) and are resistant to LPS-induced death (7,8). However, the study by MacMicking and colleagues (7) also suggested that an inducible NOS-independent pathway contributes to LPS-induced hypotension and death, and we hypothesize that one potential pathway involves heme oxygenase (HO).HO is the enzyme that generates carbon monoxide (CO) and biliverdin (subsequently reduced to bilirubin) in the course of heme metabolism (9). CO is a gas molecule that shares some of the properties of NO, inasmuch as CO binds to the heme moiety of cytosolic guanylyl cyclase to produce cGMP (10). Two distinct forms of heme oxygenase have been identified (9): HO-1 (an inducible isozyme) and HO-2 (a non-inducible isozyme). Morita and colleagues (11) have demonstrated that HO-...

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Does carbon monoxide have a physiological function?

Cited by 404 publications

References 19 publications

In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins

In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins

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

Induction of Heme Oxygenase-1 Expression in Vascular Smooth Muscle Cells

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