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Cardiovascular Research 1999 41(2):385-394; doi:10.1016/S0008-6363(98)00278-8
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Heme oxygenase–carbon monoxide signalling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide?

Richard C.M. Siow, Hideyo Sato1,1 and Giovanni E. Mann*

Vascular Biology Research Centre, School of Biomedical Sciences, King's College London, Campden Hill Road, London W8 7AH, UK

* Corresponding author. Tel.: +44-171-333-4450; fax: +44-171-333-4450; e-mail: giovanni.mann@kcl.ac.uk

Atherosclerosis is a major contributor to cardiovascular disease, and genetic disorders of lipoprotein metabolism are recognized risk factors in atherogenesis. The gaseous monoxides nitric oxide (NO) and carbon monoxide (CO), generated within the blood vessel wall, have been identified as important cellular messengers involved in the regulation of vascular smooth muscle tone. Microsomal heme oxygenases degrade heme to biliverdin and CO, and the cytosolic enzyme biliverdin reductase then catalyzes reduction of biliverdin to bilirubin, both powerful chain-breaking antioxidants. Two principal isozymes of heme oxygenase have been identified, a constitutive isoform HO-2 (Mr~34 000) and an inducible isoform HO-1 (Mr~32 000), which is expressed at a low basal level in vascular endothelial and smooth muscle cells and is induced by heavy metals, oxidative stress, inflammatory mediators and oxidized low density lipoproteins. Although NO and CO modulate intracellular cGMP levels, platelet aggregation and smooth muscle relaxation, CO has a much lower affinity for soluble guanylyl cyclase than NO. Decreased production or sensitivity to NO in atherosclerosis may be compensated for by an induction of HO-1, with bilirubin acting as a cellular antioxidant and CO as a vasodilator. This review examines the evidence that oxidized low density lipoproteins (LDL), hypoxia and pro-inflammatory cytokines induce HO-1 expression and activity in vascular endothelial and smooth muscle cells, and evaluates the anti-atherogenic potential of the heme oxygenase signalling pathway.

KEYWORDS Atherosclerosis; Heme oxygenase; Carbon monoxide; Vascular smooth muscle; Endothelium; Oxidative stress protein; Antioxidant; Nitric oxide

1 Present address: Department of Biochemistry, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.


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