Nitric Oxide-inducible Expression of Heme Oxygenase-1 in Human Cells

Bouton, Cécile; Demple, Bruce

doi:10.1074/jbc.275.42.32688

Cited by 118 publications

(29 citation statements)

References 49 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…9), is significantly less effective than DEA/NO (amount of NO release ϭ 10.1 M ϫ s) at stimulating an early increase HO-1 expression and heme oxygenase activity. This is in line with and partially explained by previous findings showing that, compared with treatment with slow NO releasers, a burst of NO considerably extends the half-life of HO-1 mRNA in human fibroblasts, suggesting that translationindependent mRNA stability could be an important mechanism by which cells sense the NO challenge (62). Notably, our data seem to indicate that NO Ϫ is less harmful than NO because exposure of cells to AS did not result in any detectable reduction in cell metabolism, whereas DEA/NO, which has a half-life similar to that of AS, caused a significant decline in this parameter.…”

Section: Discussionsupporting

confidence: 75%

Induction of Heme Oxygenase 1 by Nitrosative Stress

Naughton

Foresti

Bains

et al. 2002

Journal of Biological Chemistry

106

View full text Add to dashboard Cite

Heme oxygenase, the rate-limiting step in heme degradation to CO and bilirubin, exists in inducible (HO-1) 1 and constitutive (HO-2 and HO-3) isoforms, the synthesis and activities of which are differentially regulated in mammalian tissues (1-3). The common conception that these enzymes are merely components of a catabolic pathway that facilitates the elimination of toxic products from the organism has been disputed by strong evidence demonstrating that endogenously generated CO and bilirubin act as crucial effector molecules in the mitigation of vascular and cellular dysfunction (4 -12). Disparate conditions and a number of pathological states including hypoxia, endotoxic shock, atherosclerosis, and inflammation have been found to promote overexpression of the HO-1 gene and increased heme oxygenase activity (13-18). Although the molecular mechanism(s) leading to HO-1 induction by these and other conditions remains to be fully elucidated, a common denominator that characterizes the prompt stimulation of HO-1 under most circumstances is the transient decrease in cellular glutathione levels and a drastic change in the redox status of the intracellular milieu (15, 19 -21). It is not surprising, therefore, that conditions associated with increased production of reactive oxygen species and reactive nitrogen species (RNS) favor the activation of the HO-1/CO/bilirubin pathway, which is now regarded as an important cellular stratagem to counteract and resist different stress insults (3,22). In the context of redox reactions and signal transduction events that elicit the expression of HO-1 in vascular tissue, the gaseous molecule NO has recently been highlighted as an important biological modulator (see reviews in Refs. 22 and 23; Refs. 15 and 24). NO has been implicated in a wide range of processes critical to normal functions in the cardiovascular, nervous, and immune systems; the cytotoxic nature of NO has also been extensively emphasized when excessive production of this gas is triggered under certain pathological conditions (25). The conception that HO-1 might function to counteract the potential toxic effects evoked by NO first emerged from the discovery that certain NO-releasing agents can stimulate an increase in HO-1 transcript and heme oxygenase activity, resulting in protection against oxidative stress (26 -28). Subsequent reports have confirmed these findings (24, 29 -31), and more recent works have established that NO-related species (such as peroxynitrite and S-nitrosoglutathione) as well as endogenously generated NO and S-nitrosothiols are also capable of 32). In light of the rather complex and diverse chemistry of the NO group, which enables it to exist in a variety of interrelated redox-activated forms, investigations are now required to explore which additional NO * This work was supported by British Heart Foundation Grants PG/ 1999-005 and PG/2001-037 (to R. M.) and PG/2000 and by funds from the Dunhill Medical Trust. The National Heart Research Fund and the Wellcome Trust provided travel grants to p...

show abstract

Section: Discussionsupporting

confidence: 75%

Induction of Heme Oxygenase 1 by Nitrosative Stress

Naughton

Foresti

Bains

et al. 2002

Journal of Biological Chemistry

106

View full text Add to dashboard Cite

show abstract

“…Proinflammatory stimuli, including oxidized low-density lipoprotein, cytokines, and NO induce HO-1 gene expression (20,21,(23)(24)(25)(26). Of note, the mechanism of HO-1 induction by LNO 2 appears to be distinct from these other stimuli and may also account for some component of the HO-1-inducing actions of these stimuli, in as much as these stimuli can include or induce fatty acid nitration products.…”

Section: Discussionmentioning

confidence: 99%

Fatty acid transduction of nitric oxide signaling: Nitrolinoleic acid potently activates endothelial heme oxygenase 1 expression

Wright¹,

Schöpfer

Baker

et al. 2006

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

120

View full text Add to dashboard Cite

Recently, it has been observed that reactions between NO-derived species, unsaturated fatty acids, and lipid oxidation intermediates yield fatty acid oxidation and nitration products (2, 3). Nitroalkene derivatives of all principal unsaturated fatty acids are present in human blood and urine and represent an abundant pool of bioactive oxides of nitrogen, with tissue levels of these species influenced by endogenous redox reactions and dietary intake of nitrated lipids. Nitrolinoleic acid (10-and 12-nitro-9,12-octadecadienoic acid, LNO 2 ) is present in plasma and red blood cell membranes at concentrations of Ϸ500 nM (3). Nitroalkene fatty acid derivatives induce adaptive antiinflammatory responses by means of induction of cGMPdependent and cGMP-independent cell signaling reactions that result in inhibition of platelet and neutrophil activation (4, 5), vessel relaxation (6), and activation of peroxisome proliferatoractivated receptor (PPAR)-dependent gene expression (7).Vascular tissues maintain viability during inflammation by eliciting adaptive and protective responses. Recent studies have shown that heme oxygenase 1 (HO-1) plays a central role in vascular inflammatory signaling reactions and mediates a protective response in several inflammatory diseases, including atherosclerosis, acute renal failure, vascular restenosis, transplant rejection, and sepsis (reviewed in ref. 8). HO-1, a 32-kDa enzyme, is the ratelimiting step in the degradation of heme, yielding biliverdin, carbon monoxide, and iron (9). Biliverdin is subsequently converted to bilirubin by biliverdin reductase. All heme catabolites can contribute to integrative protective responses to oxidative stress (10). Specifically, HO activity reduces levels of prooxidative heme (11), with the iron released from heme catabolism rendered largely redox-inactive by ferritin sequestration. Ferritin is often coinduced with HO-1 and also displays cytoprotective functions (12). Heme degradation serves as the major endogenous source of carbon monoxide, a gas isoelectronic with NO that displays antiinflammatory, antiapoptotic, vasodilatory, and immune modulatory functions (13-15). The porphyrin metabolites biliverdin and bilirubin also scavenge reactive oxygen species (16,17). Finally, HO-1 induction is associated with concomitant up-regulation of the cell-cycle regulatory protein p21, which mediates antiapoptotic signaling during oxidative injury (18). Biliverdin, bilirubin, and carbon monoxide, acting individually or in concert, exert protective effects in vitro and in vivo in animal models of inflammatory injury (19).Because both nitroalkenes and HO-1 are emerging as key mediators of adaptive inflammatory responses, the impact of LNO 2 on HO-1 gene expression was examined. Herein, the marked up-regulation of HO-1 gene expression by LNO 2 in vascular cells is reported, with this induction occurring primarily at the transcriptional level. We conclude that LNO 2 mediates the induction of HO-1 by means of PPAR␥-independent and both NO-dependent and NO-independent mec...

show abstract

“…Notwithstanding, exposure to LSS delayed HO-1 mRNA degradation, a response enhanced by atorvastatin. Moreover, NO may act to stabilize HO-1 mRNA (53) and is a likely regulator of the post-transcriptional effect observed. Thus, we propose that exposure of LSS-conditioned vascular endothelium to atorvastatin results in sustained Akt phosphorylation, KLF2 and Nrf2 activation, increased eNOS activity, and both transcriptional and post-transcriptional events leading to optimal HO-1 induction and resistance to oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Induction of the Cytoprotective Enzyme Heme Oxygenase-1 by Statins Is Enhanced in Vascular Endothelium Exposed to Laminar Shear Stress and Impaired by Disturbed Flow

Ali

Zakkar

Karu

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

In addition to cholesterol-lowering properties, statins exhibit lipid-independent immunomodulatory, anti-inflammatory actions. However, high concentrations are typically required to induce these effects in vitro, raising questions concerning therapeutic relevance. We present evidence that endothelial cell sensitivity to statins depends upon shear stress. Using heme oxygenase-1 expression as a model, we demonstrate differential heme oxygenase-1 induction by atorvastatin in atheroresistant compared with atheroprone sites of the murine aorta. In vitro, exposure of human endothelial cells to laminar shear stress significantly reduced the statin concentration required to induce heme oxygenase-1 and protect against H 2 O 2 -mediated injury. Synergy was observed between laminar shear stress and atorvastatin, resulting in optimal expression of heme oxygenase-1 and resistance to oxidative stress, a response inhibited by heme oxygenase-1 small interfering RNA. Moreover, treatment of laminar shear stress-exposed endothelial cells resulted in a significant fall in intracellular cholesterol. Mechanistically, synergy required Akt phosphorylation, activation of Kruppel-like factor 2, NF-E2-related factor-2 (Nrf2), increased nitric-oxide synthase activity, and enhanced HO-1 mRNA stability. In contrast, heme oxygenase-1 induction by atorvastatin in endothelial cells exposed to oscillatory flow was markedly attenuated. We have identified a novel relationship between laminar shear stress and statins, demonstrating that atorvastatin-mediated heme oxygenase-1-dependent antioxidant effects are laminar shear stress-dependent, proving the principle that biomechanical signaling contributes significantly to endothelial responsiveness to pharmacological agents. Our findings suggest statin pleiotropy may be suboptimal at disturbed flow atherosusceptible sites, emphasizing the need for more specific therapeutic agents, such as those targeting Kruppel-like factor 2 or Nrf2.The efficacy of 3-hydroxy-3-methylglutaryl-coenzyme A reductase antagonists (statins) in reducing low density lipoprotein cholesterol, cardiovascular morbidity, and mortality is widely recognized (1). The observation that beneficial actions of statins on vascular function are detectable prior to any fall in serum cholesterol, extend to normocholesterolemic patients and exceed those of other lipid-lowering drugs despite comparable falls in total cholesterol (2, 3), suggest the existence of low density lipoprotein-cholesterol-independent effects (4, 5). Judging from in vitro studies, these may include immunomodulatory, antiinflammatory, anti-adhesive, anti-thrombotic, and cytoprotective actions (6). However, the experimental work demonstrating these pleiotropic effects has predominantly used statin concentrations exceeding those achieved by therapeutic dosing, raising questions concerning clinical relevance (4).Heme oxygenase-1 (HO-1) 2 acts as the rate-limiting factor in the catabolism of heme into biliverdin, releasing free iron and carbon monoxide (CO). Biliverdin is subs...

show abstract

Nitric Oxide-inducible Expression of Heme Oxygenase-1 in Human Cells

Cited by 118 publications

References 49 publications

Induction of Heme Oxygenase 1 by Nitrosative Stress

Induction of Heme Oxygenase 1 by Nitrosative Stress

Fatty acid transduction of nitric oxide signaling: Nitrolinoleic acid potently activates endothelial heme oxygenase 1 expression

Induction of the Cytoprotective Enzyme Heme Oxygenase-1 by Statins Is Enhanced in Vascular Endothelium Exposed to Laminar Shear Stress and Impaired by Disturbed Flow

Contact Info

Product

Resources

About