Heme oxygenase-1 protects the heart.

The seminal discovery of nitric oxide (NO) in the 1980s unraveled the novel concept that an endogenous production of a gaseous substance such as NO can impart diverse and critical functional effects on a wide spectrum of biological and pathological processes. Intense investigations in the chemistry and biology of NO have led to numerous fruitful discoveries, enhancing our understanding of many disease processes including cardiovascular disorders. Interestingly, though, we have known for a longer period of time that there exists another gaseous molecule, carbon monoxide (CO), which can be generated endogenously. The heme oxygenase (HO) enzyme system generates the majority of endogenous CO.1,2 Since the biochemical isolation of the HO enzyme in 1968, much of the focus of HO research has been in the study of HO in heme metabolism based on the known fact that the HO enzyme serves as the rate-limiting enzyme in the degradation of heme. However, in recent years, as a result of the emerging role of HO in a variety of biological processes, interest in HO has continued to grow beyond its role in heme metabolism and has expanded into many scientific disciplines. The recent characterization of the HO enzyme system in yeast, prokaryotic bacterial system, and plants further highlights the functional importance of a highly conserved enzyme throughout the evolution of living organisms. HO catalyzes the first and rate-limiting step in the degradation of heme to yield equimolar quantities of biliverdin IXa, CO, and iron1,2 (Figure). Biliverdin is subsequently converted to bilirubin via the action of biliverdin reductase, and free iron is promptly sequestered into ferritin. Three isoforms of HO exist; HO-1 is highly inducible whereas HO-2 and HO-3 are constitutively expressed.1,2 Heme, a major substrate of HO-1, and a variety of nonheme agents including heavy metals, cytokines, hormones, endotoxin, and heat shock are also strong inducers of HO-1 expression.1,2 This diversity of HO-1 inducers has provided further support for the speculation that HO-1, in addition to its role in heme degradation, may also play a vital function in maintaining cellular homeostasis. Furthermore, HO-1 is highly induced by a variety of agents causing oxidative stress including hydrogen peroxide, glutathione depletors, UV irradiation, endotoxin, hypoxia, and hyperoxia.1,2 One interpretation of this finding is that HO-1 can serve as a key biological molecule in the adaptation and/or defense against these oxidative and cellular stresses. Indeed, many laboratories have demonstrated that induction of endogenous HO-1 provides protection against oxidative stress in various in vivo and in vitro models.1,2 Furthermore, recent analysis of HO-1 null mice has strengthened the evolving paradigm that HO-1 is indeed an important molecule in the host’s defense against cellular stress in that HO-1 null mice exhibited increased susceptibility to endotoxin.3 Interestingly, the first human case of HO-1 deficiency was recently reported.4 Analysis of this patient’s HO-1 gene revealed complete loss of exon 2 of the maternal allele and a two-nucleotide deletion within exon 3 of the paternal allele. Importantly, the human patient deficient of HO-1 expression also exhibited significant phenotypic changes reflective of homeostasis imbalance, comparable to the HO-1 null mice. Cells derived from this HO-1– deficient patient also demonstrated increased susceptibility to oxidative stress.4 In this issue of Circulation Research, Yet et al5 demonstrate that HO-1 provides potent cytoprotection against ischemia/reperfusion tissue injury. These investigators successfully generated cardiac-specific transgenic mice overexpressing HO-1, and by using both isolated perfused heart preparation and an in vivo myocardial infarction model, the authors provide compelling evidence that indeed HO-1 overexpression can confer marked cytoprotection against ischemia/reperfusion-induced myocardial tissue injury. This study represents an elegant extension from their previous study demonstrating that in response to chronic hypoxia, HO-1 null mice exhibited increased right ventricular infarcts with organized mural thrombi and increased lipid peroxidation and oxidative damage in right ventricular cardiomyocytes when compared with wild-type HO mice.6 The cytoprotective effect of HO-1 in vascular injury is further supported by a recent report by Christou et al,7 who demonstrated an important role of HO-1 in the prevention of hypoxia-induced pulmonary hypertension. By using agonists of HO-1 induction, these authors successfully showed that in vivo enhancement of HO-1 in the rat lung can prevent the development of hypoxic pulmonary hypertension and importantly inhibited the structural remodeling of the pulmonary vessel. The mechanism(s) by which HO-1 mediates these cytoprotective effects against chronic hypoxia remains to be elucidated. However, the known vasodilating and antiproliferative actions of endogenous CO, as well as indirect effect of CO, on production of vasoconstrictors and vascular growth factors such as endothelin-1 (ET-1) and platelet-derived growth factor-B (PDGF-B) may be involved in combating chronic hypoxic stress.8 The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Correspondence to Augustine M.K. Choi, MD, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, MUH 628 NW, Pittsburgh, PA 15213. E-mail [email protected] (Circ Res. 2001;89:105-107.) © 2001 American Heart Association, Inc.