Reversal of HO‐1 related cytoprotection with increased expression is due to reactive iron

Suttner, Denise; Dennery, Phyllis A.

doi:10.1096/fasebj.13.13.1800

Cited by 374 publications

(316 citation statements)

References 56 publications

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“…Such a protective response, however, may be dependent on the relative level of HO-1 activity, where high levels of HO-1 may actually reverse cytoprotection. This has been shown to be the case in an experimental model of hyperoxia-induced oxidant stress where high HO-1 expression is associated with the accumulation of reactive iron (Suttner and Dennery, 1999).…”

Section: Heme Oxygenase and Neonatal Traumatic Brain Injurymentioning

confidence: 85%

Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

Chang

Claus

Vreman

et al. 2005

J Cereb Blood Flow Metab

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Intracranial bleeding is one of the most prominent aspects in the clinical diagnosis and prognosis of traumatic brain injury (TBI). Substantial amounts of blood products, such as heme, are released because of traumatic subarachnoid hemorrhages, intraparenchymal contusions, and hematomas. Despite this, surprisingly few studies have directly addressed the role of blood products, in particular heme, in the setting of TBI. Heme is degraded by heme oxygenase (HO) into three highly bioactive products: iron, bilirubin, and carbon monoxide. The HO isozymes, in particular HO-1 and HO-2, exhibit significantly different expression patterns and appear to have specific roles after injury. Developmentally, differences between the adult and immature brain have implications for endogenous protection from oxidative stress. The aim of this paper is to review recent advances in the understanding of heme regulation and metabolism after brain injury and its specific relevance to the developing brain. These findings suggest novel clinical therapeutic options for further translational study.

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Section: Heme Oxygenase and Neonatal Traumatic Brain Injurymentioning

confidence: 85%

Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

Chang

Claus

Vreman

et al. 2005

J Cereb Blood Flow Metab

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“…A previous study has shown that ferroportin is downregulated at mRNA and protein levels in splenic macrophages after LPS administration in a mouse model. 39 Therefore, we questioned whether this condition would have an impact on the levels of free iron in livers of LPS-treated rats.…”

Section: Discussionmentioning

confidence: 99%

“…37 In endothelial cells, increased expression of HO-1 exerted an increased cytotoxicity due to elevated levels of catalytically active intracellular iron. 39 This indicates that endotoxic shock temporarily creates a situation where more free iron might accumulate from increased HO-1 activity, which is not accordingly sequestered into ferritin or eliminated via ferroportin at this time. Irrespective of the source of these increased free iron levels, it was important to determine whether these increased iron levels can exert deleterious effects on cellular function.…”

Section: Discussionmentioning

confidence: 99%

A novel endotoxin-induced pathway: upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction

Duvigneau

Piskernik

Haindl

et al. 2008

Laboratory Investigation

100

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Mitochondria are involved in the development of organ failure in critical care diseases. However, the mechanisms underlying mitochondrial dysfunction are not clear yet. Inducible hemoxygenase (HO-1), a member of the heat shock protein family, is upregulated in critical care diseases and considered to confer cytoprotection against oxidative stress. However, one of the products of HO-1 is Fe 2 þ which multiplies the damaging potential of reactive oxygen species catalyzing Fenton reaction. The aim of this study was to clarify the relevance of free iron metabolism to the oxidative damage of the liver in endotoxic shock and its impact on mitochondrial function. Endotoxic shock in rats was induced by injection of lipopolysaccharide (LPS) at a dose of 8 mg/kg (i.v.). We observed that the pro-inflammatory cytokine TNF-a and the liver necrosis marker aspartate aminotransferase were increased in blood, confirming inflammatory response to LPS and damage to liver tissue, respectively. The levels of free iron in the liver were significantly increased at 4 and 8 h after onset of endotoxic shock, which did not coincide with the decrease of transferrin iron levels in the blood, but rather with expression of the inducible form of heme oxygenase (HO-1). The proteins important for sequestering free iron (ferritin) and the export of iron out of the cells (ferroportin) were downregulated facilitating the accumulation of free iron in cells. The temporarily increased concentration of free iron in the liver correlated with the temporary impairment of both mitochondrial function and tissue ATP levels. Addition of exogenous iron ions to mitochondria isolated from control animals resulted in an impairment of mitochondrial respiration similar to that observed in endotoxic shock in vivo. Our data suggest that free iron released by HO-1 causes mitochondrial dysfunction in pathological situations accompanied by endotoxic shock.

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“…Under these conditions, the apoptotic action of HO-1 appears to be mediated via the release of the bile pigments, biliverdin, and bilirubin, which at high concentration are known inducers of apoptosis (Silva et al, 2001;Liu et al, 2002c). Reversal of HO-1-related cytoprotection with increased expression has also been documented in fibroblasts (Suttner and Dennery, 1999). In this instance, the cytotoxicity results from the liberation of free iron, which can generate reactive oxygen species via the Fenton reaction.…”

Section: Ho-1 and Cell Deathmentioning

confidence: 99%

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

Durante

2003

Journal Cellular Physiology

143

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Heme oxygenase-1 (HO-1) catalyzes the degradation of heme to carbon monoxide (CO), iron, and biliverdin. Biliverdin is subsequently metabolized to bilirubin by the enzyme biliverdin reductase. Although interest in HO-1 originally centered on its heme-degrading function, recent findings indicate that HO-1 exerts other biologically important actions. Emerging evidence suggests that HO-1 plays a critical role in growth regulation. Deletion of the HO-1 gene or inhibition of HO-1 activity results in growth retardation and impaired fetal development, whereas HO-1 overexpression increases body size. Although the mechanisms responsible for the growth promoting properties of HO-1 are not well established, HO-1 can indirectly influence growth by regulating the synthesis of growth factors and by modulating the delivery of oxygen or nutrients to specific target tissues. In addition, HO-1 exerts important effects on critical determinants of tissue size, including cell proliferation, apoptosis, and hypertrophy. However, the actions of HO-1 are highly variable and may reflect a role for HO-1 in maintaining tissue homeostasis. Considerable evidence supports a crucial role for HO-1 in blocking the growth of vascular smooth muscle cells (SMCs). This antiproliferative effect of HO-1 is mediated primarily via the release of CO, which inhibits vascular SMC growth via multiple pathways. Pharmacologic or genetic approaches targeting HO-1 or CO to the blood vessel wall may represent a promising, novel therapeutic approach in treating vascular proliferative disorders.

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Reversal of HO‐1 related cytoprotection with increased expression is due to reactive iron

Cited by 374 publications

References 56 publications

Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

A novel endotoxin-induced pathway: upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

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