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(Circulation Research. 2001;88:456.)
© 2001 American Heart Association, Inc.

Editorial

Atherosclerosis

Defeat of the Defense?

Ton J. Rabelink, Erik Stroes

From the Department of Vascular Medicine, University Hospital (T.J.R.), Utrecht, and Department of Vascular Medicine, Academic Medical Hospital (E.S.), Amsterdam, The Netherlands.

Correspondence to Ton J. Rabelink, Professor of Medicine, University Medical Center Utrecht, Room F02.126, PO Box 85500 3508 GA, Utrecht, The Netherlands. E-mail T.Rabelink@worldonline.nl

Key Words: heme oxygenase • atherosclerosis • oxidative stress

	Introduction

 
Heme oxygenases (HOs) are rate-limiting enzymes that catalyze the conversion of heme into equimolar amounts of biliverdin, carbon monoxide (CO), and iron.¹ Biliverdin is subsequently reduced to bilirubin pigment by biliverdin reductase.² The heme oxygenases consist of 2 major isoforms, HO-1 and HO-2. Whereas HO-2 is constitutively produced within the brain, testes, and the endothelium, HO-1 gene expression is inducible by heme, cytokines, nitric oxide (NO) donors,^{3 4 5} and agents and conditions associated with increased oxidant stress, eg, oxidized LDL and ischemia/reperfusion injury.^{6 7} HO-1 induction has been shown to have potent antioxidant effects.⁸ Indeed, HO-1 knockout mice are more sensitive toward oxidant insults,^{9 10} whereas HO-1 is upregulated in models associated with increased oxidative stress, such as sepsis, organ transplantation, and atherosclerosis.^{11 12} Increased sensitivity to oxidant injury was also one of the hallmarks of a recently described patient with HO-1 deficiency.¹³ The potential importance of HO-1 as an antioxidant system in humans is underscored by the observation that a microsatellite polymorphism in the promotor region of the HO-1 gene could be linked to the decreased inducibility of HO-1 and associated with the development of emphysema in smokers.¹⁴

The antioxidant effect of HO-1 can be explained by several mechanisms. First, HO-1 degrades the intracellular pro-oxidant heme.¹⁵ In addition, the resulting reaction product, bilirubin, can act as a potent peroxyl radical scavenger.¹⁶ In this respect, the reduction of leukocyte adhesion during oxidative stress by HO-1 induction could largely be attributed to the antioxidant effects of bilirubin.¹⁷ HO-1 also results in the generation of CO, . . . [Full Text of this Article]

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