© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Heme oxygenase–carbon monoxide signalling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide?
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 (Mr32 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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Gao and G. E. Mann Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling Cardiovasc Res, April 1, 2009; 82(1): 9 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. True, M. Olive, M. Boehm, H. San, R. J. Westrick, N. Raghavachari, X. Xu, E. G. Lynn, M. N. Sack, P. J. Munson, et al. Heme Oxygenase-1 Deficiency Accelerates Formation of Arterial Thrombosis Through Oxidative Damage to the Endothelium, Which Is Rescued by Inhaled Carbon Monoxide Circ. Res., October 26, 2007; 101(9): 893 - 901. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C.M. Siow and A. T. Churchman Adventitial growth factor signalling and vascular remodelling: Potential of perivascular gene transfer from the outside-in Cardiovasc Res, September 1, 2007; 75(4): 659 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. E. Mann, D. J. Rowlands, F. Y.L. Li, P. de Winter, and R. C.M. Siow Activation of endothelial nitric oxide synthase by dietary isoflavones: Role of NO in Nrf2-mediated antioxidant gene expression Cardiovasc Res, July 15, 2007; 75(2): 261 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ijas, K. Nuotio, J. Saksi, L. Soinne, E. Saimanen, M.-L. Karjalainen-Lindsberg, O. Salonen, S. Sarna, J. Tuimala, P. T. Kovanen, et al. Microarray Analysis Reveals Overexpression of CD163 and HO-1 in Symptomatic Carotid Plaques Arterioscler Thromb Vasc Biol, January 1, 2007; 27(1): 154 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. W. Ryter, J. Alam, and A. M. K. Choi Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications Physiol Rev, April 1, 2006; 86(2): 583 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Bolognesi, D Sacerdoti, M Di Pascoli, P Angeli, S Quarta, A Sticca, P Pontisso, C Merkel, and A Gatta Haeme oxygenase mediates hyporeactivity to phenylephrine in the mesenteric vessels of cirrhotic rats with ascites Gut, November 1, 2005; 54(11): 1630 - 1636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Gullu, D. Erdogan, D. Tok, S. Topcu, M. Caliskan, T. Ulus, and H. Muderrisoglu High Serum Bilirubin Concentrations Preserve Coronary Flow Reserve and Coronary Microvascular Functions Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2289 - 2294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Li, K. Tanaka, K. Morioka, T. Uesaka, N. Yamada, A. Takamori, M. Handa, S. Tanabe, and A. Ihaya Thymidine Phosphorylase Gene Transfer Inhibits Vascular Smooth Muscle Cell Proliferation by Upregulating Heme Oxygenase-1 and p27KIP1 Arterioscler Thromb Vasc Biol, July 1, 2005; 25(7): 1370 - 1375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kapitulnik Bilirubin: An Endogenous Product of Heme Degradation with Both Cytotoxic and Cytoprotective Properties Mol. Pharmacol., October 1, 2004; 66(4): 773 - 779. [Full Text] [PDF]
|
|
|
|
|
|
N. Stadler, R. A. Lindner, and M. J. Davies Direct Detection and Quantification of Transition Metal Ions in Human Atherosclerotic Plaques: Evidence for the Presence of Elevated Levels of Iron and Copper Arterioscler Thromb Vasc Biol, May 1, 2004; 24(5): 949 - 954. [Abstract] [Full Text]
|
|
|
|
|
|
N. Lindenblatt, R. Bordel, W. Schareck, M.D. Menger, and B. Vollmar Vascular Heme Oxygenase-1 Induction Suppresses Microvascular Thrombus Formation In Vivo Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 601 - 606. [Abstract] [Full Text]
|
|
|
|
 |
|
 F. A. D. T. G. Wagener, H.-D. Volk, D. Willis, N. G. Abraham, M. P. Soares, G. J. Adema, and C. G. Figdor Different Faces of the Heme-Heme Oxygenase System in Inflammation Pharmacol. Rev., September 1, 2003; 55(3): 551 - 571. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. D. T. G. Wagener, H. E. van Beurden, J. W. von den Hoff, G. J. Adema, and C. G. Figdor The heme-heme oxygenase system: a molecular switch in wound healing Blood, July 15, 2003; 102(2): 521 - 528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Endler, A. Hamwi, R. Sunder-Plassmann, M. Exner, T. Vukovich, C. Mannhalter, J. Wojta, K. Huber, and O. Wagner Is Low Serum Bilirubin an Independent Risk Factor for Coronary Artery Disease in Men but Not in Women? Clin. Chem., July 1, 2003; 49(7): 1201 - 1204. [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Kiemer, N. Bildner, N. C. Weber, and A. M. Vollmar Characterization of Heme Oxygenase 1 (Heat Shock Protein 32) Induction by Atrial Natriuretic Peptide in Human Endothelial Cells Endocrinology, March 1, 2003; 144(3): 802 - 812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kaneda, M. Ohno, J. Taguchi, M. Togo, H. Hashimoto, K. Ogasawara, T. Aizawa, N. Ishizaka, and R. Nagai Heme Oxygenase-1 Gene Promoter Polymorphism Is Associated With Coronary Artery Disease in Japanese Patients With Coronary Risk Factors Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1680 - 1685. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Durante Carbon monoxide and bile pigments: surprising mediators of vascular function Vascular Medicine, August 1, 2002; 7(3): 195 - 202. [Abstract] [PDF]
|
|
|
|
 |
|
 D. Morse and A. M. K. Choi Heme Oxygenase-1 . The "Emerging Molecule" Has Arrived Am. J. Respir. Cell Mol. Biol., July 1, 2002; 27(1): 8 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R D Rakhit and M S Marber Nitric oxide: an emerging role in cardioprotection? Heart, October 1, 2001; 86(4): 368 - 372. [Full Text] [PDF]
|
|
|
|
|
|
K. Ishikawa, D. Sugawara, X.-p. Wang, K. Suzuki, H. Itabe, Y. Maruyama, and A. J. Lusis Heme Oxygenase-1 Inhibits Atherosclerotic Lesion Formation in LDL-Receptor Knockout Mice Circ. Res., March 16, 2001; 88(5): 506 - 512. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Otterbein and A. M. K. Choi Heme oxygenase: colors of defense against cellular stress Am J Physiol Lung Cell Mol Physiol, December 1, 2000; 279(6): L1029 - L1037. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mayer Association of Serum Bilirubin Concentration with Risk of Coronary Artery Disease Clin. Chem., November 1, 2000; 46(11): 1723 - 1727. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Li, M. I. Venkatesan, A. Miguel, R. Kaplan, C. Gujuluva, J. Alam, and A. Nel Induction of Heme Oxygenase-1 Expression in Macrophages by Diesel Exhaust Particle Chemicals and Quinones via the Antioxidant-Responsive Element J. Immunol., September 15, 2000; 165(6): 3393 - 3401. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. AGARWAL and H. S. NICK Renal Response to Tissue Injury: Lessons from Heme Oxygenase-1 GeneAblation and Expression J. Am. Soc. Nephrol., May 1, 2000; 11(5): 965 - 973. [Abstract] [Full Text]
|
|
|
|
 |
|
 T. J. Vachharajani, J. Work, A. C. Issekutz, and D. N. Granger Heme oxygenase modulates selectin expression in different regional vascular beds Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1613 - H1617. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Rakhit, R. J. Edwards, J. W. Mockridge, A. R. Baydoun, A. W. Wyatt, G. E. Mann, and M. S. Marber Nitric oxide-induced cardioprotection in cultured rat ventricular myocytes Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1211 - H1217. [Abstract] [Full Text] [PDF]
|
|