See related article, pages 168 –173
Heme Oxygenase-1 Protects the Heart
Augustine M.K. Choi
T
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he 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 hydro-
gen 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.
Circulation Research is available at http://www.circresaha.org
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106
Circulation Research
July 20, 2001
Catalytic reaction of heme oxygenase. CO indicates carbon
monoxide.
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The mechanism(s) by which selective overexpression of
HO-1 in cardiac tissue conferred protection against ischemia/
reperfusion injury remains poorly understood. The central
issue of how HO-1 confers cytoprotection against cellular and
tissue injury remains a major enigma in the field of HO
research today and will undoubtedly continue to challenge
and frustrate researchers in the foreseeable future. How does
HO-1 confer such potent cytoprotection against ischemia/
reperfusion tissue injury? One can speculate that the three
catalytic by-products of heme catalysis by HO, namely
bilirubin, ferritin from sequestration of free iron, and CO
(Figure), all play critical roles in mediating cytoprotection
against ischemia/reperfusion tissue injury. These speculations
have been increasingly supported by experimental data (direct and indirect) in recent years. For example, the known
antioxidant bilirubin has been shown to protect isolated
perfused rat hearts.9 Although it is not know whether ferritin
can directly mediate cytoprotection against ischemia/reperfusion tissue injury, ferritin is a known cytoprotective molecule
in the vascular endothelium against oxidative stress.10 Recently, intriguing data suggest that CO may serve to protect
against ischemia/reperfusion injury in the lung.11 The mechanism by which CO may mediate this cytoprotection perhaps
is due to the potent antifibrinolytic properties of CO.11
Interestingly, Soares and colleagues demonstrated in an in
vivo vascular injury model of xenotransplantation that CO
not only can confer protection as effectively as HO-1 but can
also confer cytoprotection in the absence of HO-1.12,13 The
beneficial effects of HO-1 have also been demonstrated in
ischemia/reperfusion injury in the liver.14 It is quite plausible
that all three by-products act in concert and synergize with
each other to optimize cytoprotection, depending on cell type
and models of injury. The additive beneficial effect of these
mediators has been shown in cultured endothelial cells, with
CO and ferritin each imparting additive cytoprotection
against tumor necrosis factor- ␣ (TNF- ␣ )–induced
apoptosis.15
Whether it is ferritin, bilirubin, or CO, or all three of these
mediators, the challenge in front of us is delineating the
signaling pathways by which these molecules confer cytoprotection. The anti-inflammatory5,12,16 and antiapoptotic effects
of HO-115,17 lend some clues as to how the catalytic by-products may transduce signals to provide downstream cytoprotection against cellular stresses. For example, recent observations suggest that CO may impart potent anti-inflammatory
and antiapoptotic effects via the mitogen kinase pathway in
macrophages and endothelial cells, respectively.15,16 Importantly, these cytoprotective effects involve neither the guany-
lyl cyclase– cGMP nor the NO pathway. The cGMPindependent pathway of CO perhaps reminds us that we no
longer can assume that CO has to “compete” with NO for
guanylyl cyclase and subsequent cGMP production for physiological function. Nevertheless, the complexity of the signaling pathways by which CO imparts cytoprotection is
further highlighted by recent reports demonstrating the critical role of cGMP in mediating antifibrinolytic and antiproliferative effect of CO in ischemia/reperfusion and vascular
injury models.11,18
As observed in many physiological, biological, and toxicological systems, overzealous production of effector molecules may be counterproductive for the maintenance of
cellular and organismal homeostasis during both normal and
pathophysiological conditions. Hence, the levels of cytoprotective genes are usually induced by cellular stresses, rather
than constitutively expressed. In the case of the HO enzyme
system, ironically, at one time or another in the past (still is),
each of three catalytic by-products of heme degradation by
HO has been a known cellular toxin.19 For example, the
released iron from breakdown of heme can serve as a potent
oxidant molecule facilitating the production of hydroxyl
radicals via the Fenton reaction. Bilirubin plays an important
role in the development of kernicterus. The lethality of CO is
well known by its ability to bind to the oxygen-carrying heme
moiety of hemoglobin, dissociating oxygen and depriving
tissues of their oxygen supply; CO remains the most common
cause of poison-related deaths in the United States. Thus, the
HO enzyme system, which possesses both constitutive and
inducible isoforms, is poised and ready to “switch” the signal,
when stressed, with an appropriate level of HO-1 induction to
combat cellular stresses. Once induced, the HO-1 molecule is
uniquely qualified to thwart deleterious toxins by the liberation of bilirubin, ferritin, or CO for cellular protection.
Ample evidence now exists that HO-1 plays a critical role
in the adaptive response of cells and tissues to a variety of
stresses. There is hard work in front of us: we need to
delineate more precisely the mediators of cytoprotection of
HO-1 and the biochemical and cellular mechanism(s) by
which HO-1 or its catalytic by-products confer
cytoprotection.
Acknowledgments
The author is supported by NIH grants HL-55330, HL-60234, and
AI-42365 and an AHA Established Investigator Award.
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KEY WORDS: carbon monoxide
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bilirubin
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ferritin
Heme Oxygenase-1 Protects the Heart
Augustine M.K. Choi
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Circ Res. 2001;89:105-107
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