The heme oxygenase-carbon monoxide system: u regulator of hepatobiliary function

Suematsu, Makoto; Ishimura, Yuzuru

doi:10.1002/hep.510310102

Cited by 124 publications

(96 citation statements)

References 54 publications

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“…This might result from the fact that stress-inducible CO itself has the ability to maintain the basal microvascular perfusion through multiple vasodilatory mechanisms involving activation of cyclic guanosine monophosphate and modulation of cytochrome P450 -derived vasoconstrictors. 6,20,31 Although the inhibitory action of stress-inducible CO on the transsulfuration pathway has first been shown in the heme-overloading detoxification model of mice in the current study, a similar event occurred in acetaminopheninduced acute liver injury model of mice in which CO was overproduced through degradation of cytochrome P450 -derived heme. 5,18 Our previous study in rats suggested that another HO-derived product bilirubin but not CO has the ability to improve bile acid-dependent bile output of the post-cold ischemic liver grafts through its antioxidative action.…”

Section: Discussionmentioning

confidence: 57%

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

et al. 2008

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Carbon monoxide (CO) is a stress-inducible gas generated by heme oxygenase (HO) eliciting adaptive responses against toxicants; however, mechanisms for its reception remain unknown. Serendipitous observation in metabolome analysis in CO-overproducing livers suggested roles of cystathionine ␤-synthase (CBS) that rate-limits transsulfuration pathway and H 2 S generation, for the gas-responsive receptor. Studies using recombinant CBS indicated that CO binds to the prosthetic heme, stabilizing 6-coordinated CO-Fe(II)-histidine complex to block the activity, whereas nitric oxide (NO) forms 5-coordinated structure without inhibiting it. The CO-overproducing livers down-regulated H 2 S to stimulate HCO 3 ؊ -dependent choleresis: these responses were attenuated by blocking HO C arbon monoxide (CO) is generated from inducible heme oxygenase 1 (HO-1) and constitutive heme oxygenase 2 (HO-2), respectively, and has the ability to regulate neurovascular functions, 1,2 apoptotic responses, 3,4 and metabolism of xenobiotics and toxicants. 5,6 This gas is overproduced through increased delivery of heme as a substrate and the HO-1 induction on exposure to stressors such as hypoxia and oxidative stress. Mechanisms by which CO regulates cell functions appear to involve an activation of soluble guanylate cyclase (sGC), the enzyme that allows the gas to bind to the prosthetic heme to synthesize cyclic guanosine monophosphate as a second messenger. 1 Distinct from nitric oxide (NO) that forms 5-coordinated NO-Fe(II) complex to trigger full activation of the enzyme, CO activates this enzyme only modestly because the gas binding stabilizes 6-coordinated CO-Fe(II)-histidine complex. 7 Mitogen-activated protein kinase has also been shown to serve as a CO-responsive signal transducer. 8 Gene disruption of HO-1 increases sensitivity to overproduction of reactive oxygen species, inflammatory mediators or xenobiotic metabolism, whereas the gene transfer or CO inhalation under these circumstances suppresses such pathogenic responses. 7-9 However, direct mechanisms for the CO reception to trigger these adaptive responses of metabolism remain unknown.Because this gas has the ability to inhibit ferrous form of the prosthetic heme of enzymes, tryptophan 2,3-dioxygenase or cytochromes P450 have been considered puta-

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Section: Discussionmentioning

confidence: 57%

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

et al. 2008

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“…2C), confirming that CO is a tonic vasoconstrictor under basal conditions. This action of CO cannot be readily explained by previously identified CO receptors, such as soluble guanylyl cyclase (6)(7)(8)(9)(10)(11)(12)15) or potassium channels (13,16), both of which mediate vasodilation. Based on previous studies indicating that physiological concentrations of CO can inhibit the ability of CBS to generate vasodilatory H 2 S (17-21, 26, 27, 38), we hypothesize that endogenous CO serves as a tonic vasoconstrictor by inhibiting CBS, thus preventing the H 2 S-mediated vasodilatory response.…”

Section: Resultsmentioning

confidence: 94%

“…Thus, HO inhibitors cause cerebral vasodilation, an effect reversed by CO (14). This action of CO cannot be readily explained by previously identified CO receptors, such as soluble guanylyl cyclase (6)(7)(8)(9)(10)(11)(12)15) or potassium channels (13,16), both of which mediate vasodilation. The CO and NO systems interface; thus, the vasodilatory actions of HO inhibitors are partially reversed by inhibitors of NOS (14).…”

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confidence: 97%

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Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Morikawa

Kajimura

Nakamura

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Enhancement of cerebral blood flow by hypoxia is critical for brain function, but signaling systems underlying its regulation have been unclear. We report a pathway mediating hypoxia-induced cerebral vasodilation in studies monitoring vascular disposition in cerebellar slices and in intact mouse brains using two-photon intravital laser scanning microscopy. In this cascade, hypoxia elicits cerebral vasodilation via the coordinate actions of H 2 S formed by cystathionine β-synthase (CBS) and CO generated by heme oxygenase (HO)-2. Hypoxia diminishes CO generation by HO-2, an oxygen sensor. The constitutive CO physiologically inhibits CBS, and hypoxia leads to increased levels of H 2 S that mediate the vasodilation of precapillary arterioles. Mice with targeted deletion of HO-2 or CBS display impaired vascular responses to hypoxia. Thus, in intact adult brain cerebral cortex of HO-2-null mice, imaging mass spectrometry reveals an impaired ability to maintain ATP levels on hypoxia.gas biology | neurovascular unit | energy metabolism | gasotransmitter T he cerebral circulation is maintained by autoregulation, which prevents marked alterations in response to changes in blood pressure, whereas functional hyperemia links blood flow to neural activity (1). Blood flow regulation in the brain is modulated by O 2 (2), with increased cerebral blood flow in response to hypoxia critical for protecting the brain against diverse insults. Such regulation also participates in functional hyperemia, as demonstrated by functional MRI investigations indicating a transient decrease in O 2 levels preceding activation of blood flow in response to neuronal firing (3).Alterations in cerebral blood flow in response to hypoxia and neural activity are mediated via several neurotransmitter systems, with prominent involvement of the gaseous mediator nitric oxide (NO) (1, 2). In response to glutamate acting on NMDA receptors, neuronal NO synthase (nNOS) is activated by increases in intracellular calcium, with the generated NO stimulating soluble guanylyl cyclase, thereby increasing cGMP levels to dilate blood vessels (4). Functional hyperemia is decreased by ∼50% in rats in response to inhibition of nNOS (5). Another gaseous mediator, CO (6-8), is also vasoactive. In some blood vessel systems (e.g., liver sinusoids), CO causes vasodilation, and inhibition of its biosynthetic enzyme HO-2 leads to vasoconstriction (9-13). However, in the cerebral circulation, CO elicits vasoconstriction. Thus, HO inhibitors cause cerebral vasodilation, an effect reversed by CO (14). This action of CO cannot be readily explained by previously identified CO receptors, such as soluble guanylyl cyclase (6-12, 15) or potassium channels (13, 16), both of which mediate vasodilation. The CO and NO systems interface; thus, the vasodilatory actions of HO inhibitors are partially reversed by inhibitors of NOS (14). A third gaseous mediator, H 2 S, is also vasoactive, eliciting vasodilation in both the peripheral and cerebral circulation (17-21). H 2 S can be physiologically ...

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“…In mammalian systems, where electrons are supplied by NADPH through NADPH-cytochrome P450 reductase (2), HO is the enzyme responsible for excess heme degradation (1) and iron recycling (3). The product CO has been implicated as a messenger molecule in various physiological functions (4,5). Although most of the structural and functional studies have been conducted on the soluble, truncated form of isoform-1 of mammalian heme oxygenase, HO-1 (6 -8), the enzyme is also present in some pathogenic bacteria where it is essential for heme-based iron acquisition from a host lacking in free extracellular iron (9 -11).…”

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confidence: 99%

Crystal Structure of the Dioxygen-bound Heme Oxygenase from Corynebacterium diphtheriae

Unno

Matsui

Chu

et al. 2004

Journal of Biological Chemistry

100

171

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HmuO, a heme oxygenase of Corynebacterium diphtheriae, catalyzes degradation of heme using the same mechanism as the mammalian enzyme. The oxy form of HmuO, the precursor of the catalytically active ferric hydroperoxo species, has been characterized by ligand binding kinetics, resonance Raman spectroscopy, and x-ray crystallography. The oxygen association and dissociation rate constants are 5 M ؊1 s ؊1 and 0.22 s ؊1 , respectively, yielding an O 2 affinity of 21 M ؊1 , which is ϳ20 times greater than that of mammalian myoglobins. However, the affinity of HmuO for CO is only 3-4-fold greater than that for mammalian myoglobins, implying the presence of strong hydrogen bonding interactions in the distal pocket of

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The heme oxygenase-carbon monoxide system: u regulator of hepatobiliary function

Cited by 124 publications

References 54 publications

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Crystal Structure of the Dioxygen-bound Heme Oxygenase from Corynebacterium diphtheriae

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