J Mol Cell Cardiol 34, 12971300 (2002) doi:10.1006/jmcc.2002.2099, available online at http://www.idealibrary.com on 1 Editorial Heme-oxygenase-1: Versatile Sentinel Against Injury R. N. M. Cornelussen 1 and A. A. Knowlton 2 1 Maastricht University, Department of Physiology, Cardiovascular Research Institute, PO Box 616, 6200 MD, Maastricht, The Netherlands; 2 Cardiovascular Division, TB172, University of California, One Shields Avenue, Davis, CA 95616, USA (Received 30 July 2002, accepted for publication 30 July 2002) Heme oxygenase-1 (HO-1, also known as HSP32) catalyzes the conversion of heme into biliverdin IXa, carbon monoxide (CO) and iron. 15 HO-2, derived from an entirely different gene, also catalyzes this reaction, but is regulated differently. HO-2 is constitutively expressed with little change in the amount of the protein, except with gluco- corticoid treatment. In contrast, HO-1 is present in low amounts in cells, and is induced by a number of stresses, mostly of an oxidative nature, as well as its natural substrate, heme. HO-1 is crucial for survival, since HO-1 de®ciency leads to premature cell death and increased susceptibility to oxidative stress. 23 A growing body of evi- dence supports the protective function of HO-1 in the cell against oxidative stress. Studies using ``speci®c'' inducers of HO-1, such as hemin or porphyrin, showed better preservation of myo- cardial function after ischemia/reperfusion, a reduced infarct size in vivo and increased survival after transplantation. 3,6,9 More sophisticated experiments, using cardiac-speci®c overexpression of HO-1, also found protection against ischemia and reperfusion injury both in vitro as well as in vivo. 28,30 Lastly, a decrease of constitutive HO-1, through targeted disruption of the gene, makes the heart more vulnerable to ischemia/reperfusion injury. 31 Mechanism of Protection The attempts to unravel the mechanisms by which HO-1 confers cardioprotection are just beginning to yield understanding of the functions and effects of HO-1. HO-1 cleaves heme molecules to yield biliverdin (subsequently converted to bilirubin), free iron and CO; all three of these molecules are anti-oxidants. 15 These products are associated with the anti-in¯ammatory, anti-apoptotic and anti- proliferative functions of HO-1. For example, over- expression of HO-1 in the heart reduces infarct size as well as lipid peroxidation, levels of the proapop- totic bax, and the proin¯ammatory interleukin- 1b. 17,30 Knockout of HO-1 had the reverse effect resulting in larger infarcts and this could be partial- ly attenuated by anti-oxidant treatment. 31 The pro- tective effects of HO-1 may be attributed to the mitigation of the concentration of pro-oxidants (heme-adducts) through replacing them with anti- oxidants. The anti-apoptotic effects of HO-1 in cardiac cells 9,21 are well recognized, but whether these effects might be ascribed to alterations in apoptotic- related genes like Bcl2, Bag1 or caspases, 9,28 or to a direct effect of CO, perhaps through the p38 mitogen activated protein kinase (MAPK) signaling transduction pathway, has yet to be elucidated. 1,24 Please address all correspondence to: A. A. Knowlton, MD., Cardiovascular Division, TB172, University of California, One Shields Avenue, Davis, CA 95616, USA. Tel: 530-752-5461; Fax: 530-752-3264; E-mail: aaknowlton@ucdavis.edu 0022±2853/02/101297  04 $35.00/0 # 2002 Published by Elsevier Science Ltd.