Gene regulation of heme oxygenase-1 as a therapeutic target

doi:10.1016/S0006-2952(00)00443-3

Biochemical Pharmacology

Volume 60, Issue 8, 15 October 2000, Pages 1121-1128

https://doi.org/10.1016/S0006-2952(00)00443-3 Get rights and content

Abstract

Heme oxygenase (HO)-1 is the inducible isoform of the rate-limiting enzyme of heme degradation. HO regulates the cellular content of the pro-oxidant heme and produces catabolites with physiological functions. HO-1 is induced by a host of oxidative stress stimuli, and the activation of HO-1 gene expression is considered to be an adaptive cellular response to survive exposure to environmental stresses. Since overexpression of the HO-1 gene is also protective against the deleterious effects of experimental injuries, the specific induction of HO-1 by ‘non-stressful’ stimuli, eg. stimuli that are not associated with oxidative stress, such as adenosine 3′,5′-cyclic monophosphate or cyclic guanosine 3′,5′-monophosphate, may have important clinical implications. This review summarizes recent advances in the understanding of regulatory mechanisms of HO-1 gene expression, in particular the role of various redox-dependent and redox-independent signaling pathways. Models of experimental injuries are highlighted in which specific overexpression of the HO-1 gene either by targeted gene transfer or by pharmacological modulation has been demonstrated to provide therapeutic effects.

Section snippets

Functional significance of HO enzyme reaction and its products

The HO enzyme reaction (Fig. 1) is physiologically significant because HO degrades the pro-oxidant heme and produces equimolar amounts of catabolites, which serve regulatory and protective functions [13].

Redox signaling

It has been reported in a large number of studies that HO-1 gene expression is induced by stimuli that increase the cellular production of ROS, including heme, heavy metals, UV light, hydrogen peroxide, and lipopolysaccharide, or by stimuli that deplete cellular glutathione stores, including buthionine sulfoximine, sodium arsenite, and iodoacetamide 5, 29. Furthermore, it has been shown that scavengers of ROS, such as N-acetyl cysteine, inhibit or reduce the magnitude of HO-1 induction by

Regulatory elements of the HO-1 gene promoter

Stimulation of the HO-1 gene by most stimuli is primarily controlled at the transcriptional level, which is governed by REs localized in the promoter 5′-flanking region of the HO-1 gene. Thus, identification and characterization of inducer-dependent REs provides important information as to the mechanisms of HO-1 gene regulation. The sequence and organization of the human, rat, mouse, and chicken HO-1 genes are known, and the regulation of the promoter 5′-flanking regions has been analyzed by

HO-1 gene expression in experimental diseases and specific HO-1 activation as a therapeutic target

HO-1 is induced in a number of experimental injuries and diseases of various organs, including carrageenin-induced pleurisy [66], congestive heart failure [67], kidney reperfusion injury [68], caerulein-induced pancreatitis [69], carbon tetrachloride-induced liver injury [70], corneal inflammation [71], neurodegenerative disease [72], or ischemic stroke [73]. It has been demonstrated that activation of the endogenous HO-1 gene may be protective against the deleterious effects of stress-mediated

Conclusions

The induction of HO-1 by various forms of oxidative stress stimuli has been implicated in a number of injuries and diseases such as ischemia–reperfusion injury or inflammation. Since overexpression of the HO-1 gene provides cytoprotection against oxidative stress, the specific activation of HO-1 gene expression by pharmacological modulation may represent a novel target for therapeutic intervention.

Acknowledgements

Work in S. I.’s laboratory is supported by the Deutsche Forschungsgemeinschaft (SFB 402 A8).

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Gene regulation of heme oxygenase-1 as a therapeutic target

Abstract

Section snippets

Functional significance of HO enzyme reaction and its products

Redox signaling

Regulatory elements of the HO-1 gene promoter

HO-1 gene expression in experimental diseases and specific HO-1 activation as a therapeutic target

Conclusions

Acknowledgements

J Biol Chem

Int J Biochem

J Biol Chem

J Biol Chem

Arch Biochem Biophys

Arch Biochem Biophys

J Biol Chem

Curr Opin Cell Biol

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Biochem Pharmacol

J Biol Chem

J Hepatol

Cell

J Biol Chem

J Biol Chem

J Mol Cell Cardiol

FEBS Lett

Biochem Pharmacol

J Mol Cell Cardiol

The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase

Proc Natl Acad Sci USA

The heme oxygenase systemA regulator of second messenger gases

Annu Rev Pharmacol Toxicol

Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3

Eur J Biochem

Overexpression of heme oxygenase-1 in pulmonary epithelial cells results in cell growth arrest and increased resistance to hyperoxia

Proc Natl Acad Sci USA

Transfection of the human heme oxygenase gene into rabbit coronary microvessel endothelial cellsProtective effect against heme and hemoglobin toxicity

Proc Natl Acad Sci USA

Heme oxygenase is required for mammalian iron reutilization

Proc Natl Acad Sci USA

Reduced stress defense in heme oxygenase 1-deficient cells

Proc Natl Acad Sci USA

Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency

J Clin Invest

Pharmacological modulation of heat shock factor 1 by antiinflammatory drugs results in protection against stress-induced cellular damage

Proc Natl Acad Sci USA

Specific induction of the 70-kD heat stress proteins by the tyrosine kinase inhibitor herbimycin-A protects rat neonatal cardiomyocytes

J Clin Invest

Bioactivity of heme and its containment

Am J Hematol

Oxidative effects of heme and porphyrins on proteins and lipids

Semin Hematol

Purification, characterization and cloning of a heme-binding protein (23 kDa) in rat liver cytosol

Biochemistry

Structure–function aspects in the nitric oxide synthases

Annu Rev Pharmacol Toxicol

The heme oxygenase pathway and its interaction with nitric oxide in the control of cellular homeostasis

Free Radic Res

Bilirubin is an antioxidant of possible physiological importance

Science

Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress

Proc Natl Acad Sci USA

The heme oxygenase–carbon monoxide systemA regulator of hepatobiliary function

Hepatology

Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of haeme oxygenase-1

Br J Pharmacol

Haem oxygenase-1 prevents cell death by regulating cellular iron

Nat Cell Biol