Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation Research
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation Research. 2001;88:456-457

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rabelink, T. J.
Right arrow Articles by Stroes, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rabelink, T. J.
Right arrow Articles by Stroes, E.
Related Collections
Right arrow Animal models of human disease
Right arrow Pathophysiology
Right arrow Risk Factors
Right arrow Mechanism of atherosclerosis/growth factors
(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{at}worldonline.nl


Key Words: heme oxygenase • atherosclerosis • oxidative stress


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
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, which has antiatherogenic and vasodilating properties mediated via cGMP.18 CO also has the ability to inhibit cytochrome P-450, which can promote oxidation of fatty acids. In this respect, HO-1 could serve as a backup mechanism for the impaired NO availability during atherogenesis, when increased HO-1 expression can result in the production of bilirubin and CO.19 In this scenario, bilirubin and CO act as a cellular antioxidant and a vasodilator, respectively.

In this issue of Circulation Research, Ishikawa et al20 describe how pharmacological modulation of HO-1 can alter atherogenesis in LDL receptor knockout mice. Induction of HO-1 with hemin (±deferoxamin) resulted in smaller atherosclerotic lesions, whereas inhibition of HO-1 with Zn-protoporphyrin IX resulted in larger lesions compared with controls. This study corroborates the importance of vascular defense mechanisms against oxidant stress in the course of atherogenesis. Indeed, many key events during atherogenesis have been related to increased oxygen radical stress, including oxidative modification of lipids, induction of proinflammatory genes, increased cellular proliferation, and alterations of NO availability.21 HO-1 induction is a natural response to increased oxidative stress. However, recent data from the same group of investigators show that strong upregulation of HO-1 is not sufficient to protect the vessel wall from development of atherosclerosis.22 Therefore, the question arises as to how specific additional activation of HO-1 could be achieved in the clinical setting. Pharmacological induction of heme oxygenases in the clinical setting is very complex. Hemin, for example, may also induce lipid peroxidation and could play a detrimental role in the potential link between increased iron status and cardiovascular disease.23 Alternative procedures to obtain HO-1 induction, such as exposure to endotoxin and cytokines, certainly have their limitations. Interestingly, NO donors have recently been shown to cause HO-1 induction, most likely attributable to the activation of soluble guanylate cyclase.19 24 However, NO donors such as 3-morpholinosydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP) are characterized by simultaneous release of both reactive nitrogen and oxygen species. Therefore, comparable to the setting of atherosclerosis, HO-1 induction by these drugs may to some extent also reflect a response to redox activation. Nevertheless, modulation of vascular cGMP, either by NO donors, by cGMP itself, or by the natriuretic peptides, presently seems to be the most promising tool to pharmacologically modulate HO-1 induction. HO-1 could also be considered a target for local vascular gene therapy. In obese Zucker rats, HO-1 transduction has been shown to attenuate ischemia/reperfusion injury and to prolong survival after liver transplantation.25 It is certain, however, that additional studies are needed to extrapolate this finding to (local) atherogenesis and neointimal hyperplasia.

Unfortunately, the present study by Ishikawa et al20 does not offer insight into the mechanisms responsible for HO-1–related effects. Both the reduction in lipid peroxidation and the increase in NO bioavailability could be the result of an antioxidant effect. However, the mechanism responsible for this antioxidant effect was not addressed in the study by Ishikawa et al.20 Additional elucidation of this mechanism may provide the key to a deeper understanding of the failure of this defense system during atherogenesis (despite its upregulation).22 One interesting hypothesis is that NO requires adequate antioxidant mechanisms to be able to exert its actions. Indeed, the reaction coefficient of NO and superoxide exceeds that of the enzymatic antioxidant systems, making NO availability dependent on the level of oxyradical stress. In this respect, it makes sense that NO induces enzymatic antioxidant systems, such as HO-1 and extracellular superoxide dismutase (SOD).26 As a consequence, it can be argued that the efficacy of the antioxidant defense systems in counteracting atherosclerosis is critically dependent on the prevailing NO status.

In conclusion, the HO system has come a long way, from an enzyme predominantly responsible for heme degradation to a potential defense mechanism against the development of atherosclerosis. Although most of our clinical efforts in the treatment of atherosclerosis presently focus on reducing risk factors, ie, reducing the insults to the vascular wall, the study by Ishikawa et al20 reemphasizes the potential of targeting oxyradical defense mechanisms in prevention of cardiovascular disease.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 up arrowIntroduction
 *References
 

  1. Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997;37:517–554.[Medline] [Order article via Infotrieve]
  2. Tenhunen R, Marver HS, Schmid R. Microsomal heme oxygenase: characterization of the enzyme. J Biol Chem. 1969;244:6388–394.[Abstract/Free Full Text]
  3. Choi AMK, Alam J. Heme oxygenase-1: function, regulation and implication of a novel stress inducible protein in oxidant induced lung injury. Am J Respir Cell Mol Biol. 1996;15:9–19.[Abstract]
  4. Rizzardini M, Terao M, Falciani F, Cantoni L. Cytokine induction of haem oxygenase mRNA in mouse liver: interleukin 1 transcriptionally activates the haem oxygenase gene. Biochem J. 1993;290:343–347.
  5. Durante W, Kroll MH, Christodoulides N, Peyton KJ, Schafer AI. Nitric oxide induces heme oxygenase 1 gene expression and carbon monoxide production in vascular smooth muscle cells. Circ Res. 1997;80:557–564.[Abstract/Free Full Text]
  6. Ishikawa K, Navab M, Leitingen AM, Lusis AJ. Induction of heme oxygenase 1 inhibits monocyte transmigration induced by mildly oxidized LDL. J Clin Invest. 1997;100:1209–1216.[Medline] [Order article via Infotrieve]
  7. Siow RC, Ishii T, Sato H, Taketani S, Leake DS, Sweiry JH, Peason JD, Bannai S, Mann GE. Induction of the antioxidant stress proteins heme oxygenase 1 and MSP23 by stress agents and oxidized LDL in cultured vascular smooth muscle cells. FEBS Lett. 1995;368:239–242.[Medline] [Order article via Infotrieve]
  8. Stocker R. Induction of heme oxygenase as a defence against oxidative stress. Free Radic Res Commun. 1990;9:101–112.[Medline] [Order article via Infotrieve]
  9. Wiesel P, Patel AP, DiFonzo N, Marria PB, Sim CU, Pellacani A, Maemura K, LeBlanc BW, Marino K, Doerschuk CM, Yet SF, Lee ME, Perrella MA. Endotoxin-induced mortality is related to increased oxidative stress and end-organ dysfunction, not refractory hypotension, in heme oxygenase-1–deficient mice. Circulation. 2000;102:3015–3022.[Abstract/Free Full Text]
  10. Poss KD, Tonegawa S. Reduced stress defense in heme oxygenase-1 deficient cells. Proc Natl Acad Sci U S A. 1997;94:10925–10930.[Abstract/Free Full Text]
  11. Agarwall A, Nick HS. Renal response to tissue injury: lessons from heme oxygenase 1 gene ablation and expression. J Am Soc Nephrol. 2000;11:965–973.[Abstract/Free Full Text]
  12. Wang LJ, Lee TS, Lee FY, Pai RC, Chau LY. Expression of heme oxygenase 1 in atherosclerotic lesions. Am J Pathol. 1998;152:711–720.[Abstract]
  13. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase 1 deficiency. J Clin Invest. 1999;103:129–135.[Medline] [Order article via Infotrieve]
  14. Yamada N, Yamaya M, Okinaga S, Nakayama K, Sekizawa K, Shibahara S, Sasaki H. Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema. Am J Hum Genet. 2000;66:187–195.[Medline] [Order article via Infotrieve]
  15. Balla J, Jacob HS, Balla G, Nath KA, Eaton JW, Vercellotti GM. Endothelial cell heme uptake from heme proteins: sensitization and desensitization to oxidant damage. Proc Natl Acad Sci U S A. 1993;90:9285–9289.[Abstract/Free Full Text]
  16. Llesuy SF, Tomaro ML. Heme oxygenase and oxidative stress: evidence of involvement of bilirubin as physiological protector against oxidative damage. Biochim Biophys Acta. 1994;1223:9–14.[Medline] [Order article via Infotrieve]
  17. Hayashi S, Takamiya R, Yamaguchi T, Matsumoto K, Tojo SJ, Tamatani T, Kitajima M, Makino N, Ishimura Y, Suematsu M. Induction of heme oxygenase-1 suppresses venular leukocyte adhesion elicited by oxidative stress: role of bilirubin generated by the enzyme. Circ Res. 1999;85:663–671.[Abstract/Free Full Text]
  18. Morita T, Kourembanas S. Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell derived carbon monoxide. J Clin Invest. 1995;96:2676–2682.
  19. Polte T, Abate A, Dennery PA, Schröder H. Heme oxygenase-1 is a cGMP-inducible endothelial protein and mediates the cytoprotective action of nitric oxide. Arterioscler Thromb Vasc Biol. 2000;20:1209–1215.[Abstract/Free Full Text]
  20. Ishikawa K, Sugawara D, Wang X-p, Suzuki K, Itabe H, Maruyama Y, Lusis AJ. Heme oxygenase-1 inhibits atherosclerotic lesion formation in LDL receptor knockout mice. Circ Res. 2001;88:506–512.[Abstract/Free Full Text]
  21. O’Donnell VB, Freeman BA. Interactions between nitric oxide and lipid oxidation pathways: implications for vascular disease. Circ Res. 2001;88:12–21.[Abstract/Free Full Text]
  22. Shi W, Wang NJ, Shih DM, Sun VZ, Wang X, Lusis AJ. Determinants of atherosclerosis susceptibility in the C3H and C57BL/6 mouse model: evidence for involvement of endothelial cells but not blood cells or cholesterol metabolism. Circ Res. 2000;86:1078–1084.[Abstract/Free Full Text]
  23. Danesh J, Appleby P. Coronary heart disease and iron status: meta-analyses of prospective studies. Circulation. 1999;99:852–854.[Abstract/Free Full Text]
  24. Hara E, Takahashi K, Takeda K, Nakayama M, Yoshizawa M, Fujita H, Shirato K, Shibahara S. Induction of heme oxygenase-1 as a response in sensing the signals evoked by distinct nitric oxide donors. Biochem Pharmacol. 1999;58:227–236.[Medline] [Order article via Infotrieve]
  25. Amersi F, Buelow R, Kato H, Ke B, Coite AJ, Shen KD, Zhao D, Zaky J, Melinek J, Lassman DG, Ghobrial RM, Busuttil RW, Kupiec-Weglinsky JW. Upregulation of hem oxygenase 1 protects genetically fat Zucker rat livers from ischemia reperfusion injury. J Clin Invest. 1999;104:1631–1639.[Medline] [Order article via Infotrieve]
  26. Fukai T, Siegfried MR, Ushio-Fukai M, Cheng Y, Kojda G, Harrison DG. Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. J Clin Invest. 2000;105:1631–1639.[Medline] [Order article via Infotrieve]



This article has been cited by other articles:


Home page
 HypertensionHome page
B. Braam, R. de Roos, H. Bluyssen, P. Kemmeren, F. Holstege, J. A. Joles, and H. Koomans
Nitric Oxide-Dependent and Nitric Oxide-Independent Transcriptional Responses to High Shear Stress in Endothelial Cells
Hypertension, April 1, 2005; 45(4): 672 - 680.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rabelink, T. J.
Right arrow Articles by Stroes, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rabelink, T. J.
Right arrow Articles by Stroes, E.
Related Collections
Right arrow Animal models of human disease
Right arrow Pathophysiology
Right arrow Risk Factors
Right arrow Mechanism of atherosclerosis/growth factors

Circulation Research Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2001 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.