This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ishikawa, K. Articles by Maruyama, Y. Search for Related Content PubMed PubMed Citation Articles by Ishikawa, K. Articles by Maruyama, Y. Related Collections Animal models of human disease Pathophysiology Mechanism of atherosclerosis/growth factors

(Circulation. 2001;104:1831.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Heme Oxygenase-1 Inhibits Atherogenesis in Watanabe Heritable Hyperlipidemic Rabbits

Kazunobu Ishikawa, MD; Daisuke Sugawara, MD; Jun Goto, MD; Yasuyuki Watanabe, MD; Keiichi Kawamura, MD; Masashi Shiomi, PhD; Hiroyuki Itabe, PhD; Yukio Maruyama, MD

From the First Department of Internal Medicine, Fukushima Medical University, Fukushima (K.I., D.S., J.G., Y.W., K.K., Y.M.); the Institute for Experimental Animals, Kobe University School of Medicine, Kobe (M.S.); and the Department of Microbiology and Molecular Pathology, Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa (H.I.), Japan.

Correspondence to Yukio Maruyama, MD, First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan 960-1295. E-mail maruyama{at}fmu.ac.jp

Background— Heme oxygenase-1 (HO-1) is proposed to have a variety of adaptive responses against oxidative stress. To examine the function of HO-1 against atherogenesis in vivo, we observed the effects of HO-1 inhibition on atherosclerotic lesion formation in Watanabe heritable hyperlipidemic rabbits (WHHL).

Methods and Results— During 4 weeks of a 1% cholesterol diet, intravenous injections of Sn-protoporphyrin IX to inhibit HO-1 (S group, n=10) and saline as a control (C group, n=10) were given to 3-month-old WHHL rabbits. The percentages of en face atherosclerotic lesion areas in total descending aorta by Sudan IV staining (EFA) and the ratio of intima to media in microscopic atherosclerotic lesions in the ascending aortas (I/M) were calculated. Two different quantitative methods revealed significantly greater atherosclerotic lesions in the S group than the C group (EFA, P<0.001; I/M, P<0.005). HO-1 expression in atherosclerotic lesions was confirmed by Northern blot and immunohistochemical analyses. The dominant cell types expressing HO-1 were macrophages and foam cells, in which oxidized phospholipids were also accumulated. HO inhibition increased plasma and tissue lipid peroxide levels without affecting plasma lipid co osition.

Conclusions— These results suggest the possibilities that HO-1 has antiatherogenic properties in vivo and that the antiatherogenic properties of HO-1 are conducted through the prevention of lipid peroxidation.

Key Words: heme oxygenase • hypercholesterolemia • atherosclerosis

This article has been cited by other articles:

				Y. Wei, X.-m. Liu, K. J. Peyton, H. Wang, F. K. Johnson, R. A. Johnson, and W. Durante Hypochlorous acid-induced heme oxygenase-1 gene expression promotes human endothelial cell survival Am J Physiol Cell Physiol, October 1, 2009; 297(4): C907 - C915. [Abstract] [Full Text] [PDF]

				C. Cheng, A. M. Noordeloos, V. Jeney, M. P. Soares, F. Moll, G. Pasterkamp, P. W. Serruys, and H. J. Duckers Heme Oxygenase 1 Determines Atherosclerotic Lesion Progression Into a Vulnerable Plaque Circulation, June 16, 2009; 119(23): 3017 - 3027. [Abstract] [Full Text] [PDF]

				G. Korosoglou, R. G. Weiss, D. A. Kedziorek, P. Walczak, W. D. Gilson, M. Schar, D. E. Sosnovik, D. L. Kraitchman, R. C. Boston, J. W.M. Bulte, et al. Noninvasive Detection of Macrophage-Rich Atherosclerotic Plaque in Hyperlipidemic Rabbits Using "Positive Contrast" Magnetic Resonance Imaging J. Am. Coll. Cardiol., August 5, 2008; 52(6): 483 - 491. [Abstract] [Full Text] [PDF]

				N. G. Abraham and A. Kappas Pharmacological and Clinical Aspects of Heme Oxygenase Pharmacol. Rev., March 1, 2008; 60(1): 79 - 127. [Abstract] [Full Text] [PDF]

				T. S. Perlstein, R. L. Pande, J. A. Beckman, and M. A. Creager Serum Total Bilirubin Level and Prevalent Lower-Extremity Peripheral Arterial Disease: National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 Arterioscler Thromb Vasc Biol, January 1, 2008; 28(1): 166 - 172. [Abstract] [Full Text] [PDF]

				S. J. Peterson, D. Husney, A. L. Kruger, R. Olszanecki, F. Ricci, L. F. Rodella, A. Stacchiotti, R. Rezzani, J. A. McClung, W. S. Aronow, et al. Long-Term Treatment with the Apolipoprotein A1 Mimetic Peptide Increases Antioxidants and Vascular Repair in Type I Diabetic Rats J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 514 - 520. [Abstract] [Full Text] [PDF]

				L. D. Orozco, M. H. Kapturczak, B. Barajas, X. Wang, M. M. Weinstein, J. Wong, J. Deshane, S. Bolisetty, Z. Shaposhnik, D. M. Shih, et al. Heme Oxygenase-1 Expression in Macrophages Plays a Beneficial Role in Atherosclerosis Circ. Res., June 22, 2007; 100(12): 1703 - 1711. [Abstract] [Full Text] [PDF]

				N. Hill-Kapturczak and A. Agarwal Haem oxygenase-1--a culprit in vascular and renal damage? Nephrol. Dial. Transplant., June 1, 2007; 22(6): 1495 - 1499. [Full Text] [PDF]

				R. Stocker and M. A. Perrella Heme Oxygenase-1: A Novel Drug Target for Atherosclerotic Diseases? Circulation, November 14, 2006; 114(20): 2178 - 2189. [Full Text] [PDF]

				C. A. Schaer, G. Schoedon, A. Imhof, M. O. Kurrer, and D. J. Schaer Constitutive Endocytosis of CD163 Mediates Hemoglobin-Heme Uptake and Determines the Noninflammatory and Protective Transcriptional Response of Macrophages to Hemoglobin Circ. Res., October 27, 2006; 99(9): 943 - 950. [Abstract] [Full Text] [PDF]

				B. J. Wu, K. Kathir, P. K. Witting, K. Beck, K. Choy, C. Li, K. D. Croft, T. A. Mori, D. Tanous, M. R. Adams, et al. Antioxidants protect from atherosclerosis by a heme oxygenase-1 pathway that is independent of free radical scavenging J. Exp. Med., April 17, 2006; 203(4): 1117 - 1127. [Abstract] [Full Text] [PDF]

				H Yasuda, S Okinaga, M Yamaya, T Ohrui, M Higuchi, M Shinkawa, S Itabashi, K Nakayama, M Asada, A Kikuchi, et al. Association of susceptibility to the development of pneumonia in the older Japanese population with haem oxygenase-1 gene promoter polymorphism. J. Med. Genet., April 1, 2006; 43(4): e17 - e17. [Abstract] [Full Text] [PDF]

				L. Wu and R. Wang Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications Pharmacol. Rev., December 1, 2005; 57(4): 585 - 630. [Abstract] [Full Text] [PDF]

				T. Morita Heme Oxygenase and Atherosclerosis Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1786 - 1795. [Abstract] [Full Text] [PDF]

				S. F. Ameriso, A. R. Villamil, C. Zedda, J. C. Parodi, S. Garrido, M. I. Sarchi, M. Schultz, J. Boczkowski, and G. E. Sevlever Heme Oxygenase-1 Is Expressed in Carotid Atherosclerotic Plaques Infected by Helicobacter pylori and Is More Prevalent in Asymptomatic Subjects Stroke, September 1, 2005; 36(9): 1896 - 1900. [Abstract] [Full Text] [PDF]

				K. Kawamura, K. Ishikawa, Y. Wada, S. Kimura, H. Matsumoto, T. Kohro, H. Itabe, T. Kodama, and Y. Maruyama Bilirubin From Heme Oxygenase-1 Attenuates Vascular Endothelial Activation and Dysfunction Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 155 - 160. [Abstract] [Full Text] [PDF]

				R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]

				Y.-M. Deng, B. J. Wu, P. K. Witting, and R. Stocker Probucol Protects Against Smooth Muscle Cell Proliferation by Upregulating Heme Oxygenase-1 Circulation, September 28, 2004; 110(13): 1855 - 1860. [Abstract] [Full Text] [PDF]

				Y.-H. Chen, L.-Y. Chau, M.-W. Lin, L.-C. Chen, M.-H. Yo, J.-W. Chen, and S.-J. Lin Heme oxygenase-1 gene promotor microsatellite polymorphism is associated with angiographic restenosis after coronary stenting Eur. Heart J., January 1, 2004; 25(1): 39 - 47. [Abstract] [Full Text] [PDF]

				G. Kronke, V. N. Bochkov, J. Huber, F. Gruber, S. Bluml, A. Furnkranz, A. Kadl, B. R. Binder, and N. Leitinger Oxidized Phospholipids Induce Expression of Human Heme Oxygenase-1 Involving Activation of cAMP-responsive Element-binding Protein J. Biol. Chem., December 19, 2003; 278(51): 51006 - 51014. [Abstract] [Full Text] [PDF]

				N. Hill-Kapturczak, C. Voakes, J. Garcia, G. Visner, H. S. Nick, and A. Agarwal A cis-Acting Region Regulates Oxidized Lipid-Mediated Induction of the Human Heme Oxygenase-1 Gene in Endothelial Cells Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1416 - 1422. [Abstract] [Full Text] [PDF]

				J. F. Ndisang, L. Wu, W. Zhao, and R. Wang Induction of heme oxygenase-1 and stimulation of cGMP production by hemin in aortic tissues from hypertensive rats Blood, May 15, 2003; 101(10): 3893 - 3900. [Abstract] [Full Text] [PDF]

				X.-L. Chen, S. E. Varner, A. S. Rao, J. Y. Grey, S. Thomas, C. K. Cook, M. A. Wasserman, R. M. Medford, A. K. Jaiswal, and C. Kunsch Laminar Flow Induction of Antioxidant Response Element-mediated Genes in Endothelial Cells. A NOVEL ANTI-INFLAMMATORY MECHANISM J. Biol. Chem., January 3, 2003; 278(2): 703 - 711. [Abstract] [Full Text] [PDF]

				R. Kohen and A. Nyska Invited Review: Oxidation of Biological Systems: Oxidative Stress Phenomena, Antioxidants, Redox Reactions, and Methods for Their Quantification Toxicol Pathol, October 1, 2002; 30(6): 620 - 650. [Abstract] [PDF]