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(Circulation. 2006;114:2178-2189.)
© 2006 American Heart Association, Inc.

Basic Science for Clinicians

Heme Oxygenase-1

A Novel Drug Target for Atherosclerotic Diseases?

Roland Stocker, PhD; Mark A. Perrella, MD

From the Centre for Vascular Research, School of Medical Sciences, University of New South Wales, and Department of Haematology, Prince of Wales Hospital, Sydney, Australia (R.S.), and Pulmonary and Critical Care Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass (M.A.P.).

Correspondence to Roland Stocker, Centre for Vascular Research, School of Medical Sciences, Faculty of Medicine, University of New South Wales, UNSW Sydney, Australia. E-mail r.stocker@unsw.edu.au

Key Words: atherosclerosis • cardiovascular diseases • endothelium • inflammation • metabolism • pharmacology • vasodilation

An extract of the first 250 words of the full text is provided, because this article has no abstract.

	Introduction

 
Schmid and coworkers¹ were the first to report on the presence of heme oxygenase (HO) in liver microsomes capable of degrading heme to bilirubin, and this activity was subsequently dissociated from cytochrome P-450.^2,3 HO catalyzes the first and rate-limiting step in the oxidative degradation of heme (Fe-protoporphyrin-IX) to carbon monoxide (CO), ferrous iron (Fe²⁺), and biliverdin-IX (Figure 1). The enzyme binds heme in a 1:1 molar complex, and HO-bound heme acts as prosthetic group and substrate. The reaction requires 3 molecules of molecular oxygen (O₂) per heme molecule oxidized and reducing equivalents derived from nicotinamide adenine dinucleotide phosphate or nicotinamide adenine dinucleotide (reduced form) and transferred to the oxygenase via nicotinamide adenine dinucleotide phosphate:cytochrome P-450 reductase. Regiospecific oxidation of heme is achieved in a stepwise reaction, with -meso-hydroxyheme and verdoheme as intermediates, and the dissociation of CO followed by that of Fe²⁺.⁴ The release of biliverdin from HO is accelerated by biliverdin reductase, which reduces the green pigment to bilirubin-IX,⁴ which is then excreted into bile as the glucuronic acid conjugate.

View larger version (20K): [in this window] [in a new window]   Figure 1. Oxidative metabolism of heme by HO and biliverdin reductase, giving rise to CO, iron, biliverdin, and bilirubin.

Originally, the interest in HO was related to its well-established function in heme catabolism and the turnover of erythrocytes. For many years, CO and bilirubin were regarded as toxic waste byproducts of the HO reaction, but in 1987, a potential beneficial role of bilirubin was proposed⁵ based on the in vitro antioxidant activities of the . . . [Full Text of this Article]

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