Serial review: Heme oxygenase in human diseases Serial Review Editor: Phyllis A. Dennery
HO in pregnancy,☆☆

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Abstract

The enzyme heme oxygenase (HO) has been implicated in several physiological functions throughout the body including control of vascular tone and regulation of the inflammatory and apoptotic cascades as well as contributing to the antioxidant capabilities in several organ systems. These various properties attributed to HO are carried out through the catalytic products of heme degradation, namely carbon monoxide (CO), biliverdin, and free iron (Fe2+). As the newly emerging roles of HO in normal organ function have come to light, researchers in several disciplines have assessed the role of this enzyme in various physiological and pathological changes taking place in the human body over a lifetime. Included in this new wave of interest is the involvement of HO, and its by-products, in the normal function of the vital organ of pregnancy, the placenta. In this review the role of HO, and its catalytic products, will be examined in the context of pregnancy. The different isoforms of the HO enzyme (HO-1, HO-2, HO-3) have been localized throughout placental tissue, and have been shown to be physiologically active. The HO protein and more specifically its catalytic by-products (CO, biliverdin, and Fe2+) have been postulated to be involved in the maintenance of uterine quiescence throughout gestation, regulation of hemodynamic control within the uterus and placenta, regulation of the apoptotic and inflammatory cascades in trophoblast cells, and the maintenance of a balance of the oxidant-antioxidant status within the placental tissues. The association between this enzyme system, and its above-noted roles throughout pregnancy, with the hypertensive disorder of pregnancy preeclampsia (PET), will also be examined. It is hypothesized that a decrease in HO expression and/or activity throughout gestation would be capable of initiating several pathological processes involved in the etiology of PET. This hypothesis has led to further discussion emphasizing the possibility of novel therapeutic designs targeting this enzyme system for the treatment of PET.

Introduction

The enzyme heme oxygenase (HO) was originally characterized in 1968 by Tenhunen, and was described as the only mediator of heme metabolism in a cell [1]. This led to the notion that this enzyme was a housekeeping protein, strictly involved in maintaining homeostasis of the heme pool. Since then, great strides have been made in the areas of research surrounding heme metabolism in general and HO in particular. It is now recognized that HO is involved in the control of vascular tone [2], [3], [4], regulating anti-inflammatory [5], [6], [7] and antiapoptotic [6], [7], [8], [9] responses as well as reducing oxidative stress and subsequent tissue damage in several organ systems [10], [11], [12]. These various properties attributed to HO are carried out through the catalytic products of heme degradation, namely carbon monoxide (CO), biliverdin, and free iron (Fe2+) (Fig. 1).

Three isoforms of the HO protein have been identified. HO-1 is a 32-kDA inducible form of the enzyme; HO-2 is a 36-kDa constitutive form of the enzyme while HO-3 is the least characterized and least active of the isoforms [13], [14]. HO-1 is ubiquitously distributed in mammalian tissues but is expressed in high concentrations in the spleen and liver, areas of high erythrocyte turnover [13], [15]. HO-1 protein expression and activity have been demonstrated to be induced by several stimuli such as heme, metalloporphyrins, transition metals, cytokines, endotoxins, hyperthermia, hypoxia, and oxidants [13], [15] and as such it has been coined a stress protein. HO-2 is found in numerous tissues throughout the body, and appears to be involved in the maintenance of basal heme metabolism [13], [15]. This vast array of activating stimuli coupled with HO's antioxidant, anti-inflammatory, antiapoptotic, and regulation of vascular tone properties has led to questions about the functional significance and role of this enzyme under both physiological and pathological circumstances.

All three catalytic products of heme degradation, CO, biliverdin, and Fe2+, were originally deemed to be toxic compounds that were quickly excreted; at high enough concentrations, all three of these compounds do possess cytotoxic properties [16], [17], [18]. However, it has now been demonstrated that at the concentrations produced through the actions of HO, all three compounds instead display fairly potent cytoprotective properties.

Carbon monoxide has been demonstrated to display several of the same physiological functions as its diatomic cousin nitric oxide (NO). These functions include decreasing vascular tone via vasodilation [3], [19], inhibition of platelet aggregation [20], as well as inhibition of the apoptotic and inflammatory cascades [6], [7], [9]. Promising results are now emerging concerning the potential benefits that CO may provide to increase the success of transplanted organs.

Free heme can undergo autooxidation to produce superoxide (O2) and hydrogen peroxide (H2O2), which in turn may promote the formation of other highly toxic reactive oxygen species (ROS). The enzyme HO is thus recognized as an antioxidant, by removing free heme. In addition, the second and third catalytic products of heme degradation (biliverdin and Fe2+) contribute to HO's antioxidant effect. Biliverdin and its subsequent breakdown product bilirubin demonstrate potent antioxidant characteristics [21]. A recent description of the cycle in which biliverdin is reduced to bilirubin, via biliverdin reductase, and then is subsequently recycled back into biliverdin suggests a mechanism through which the antioxidant properties of these two molecules may be amplified in vivo [22]. Free iron, released from the core of the heme molecule, is capable of extensive cellular damage. Through the Fenton reaction it is capable of promoting the generation of damaging free radicals [23], [24]. The enzyme HO, however, is capable of interactions with intracellular iron pumps [25] as well as upregulating the generation of ferritin [26], a potent iron-chelating molecule. Therefore, while heme catabolism will initially increase levels of free iron, these additional actions of HO have the net effect of decreasing intracellular free iron and thus limit the generation of ROS. The antioxidant properties of both biliverdin/bilirubin and ferritin have been used therapeutically to ameliorate hepatic injury in several models, including ischemia/reperfusion injury [27], [28].

Section snippets

The HO enzyme and pregnancy

As the newly emerging roles of HO in normal organ function have come to light, researchers have studied this enzyme's role in various physiologic and pathologic processes taking place in the human body. Included is the involvement of HO, and its by-products, in pregnancy and specifically its role in placental function. In order for this enzyme to be recognized as a significant contributor to normal placental function three criteria must be fulfilled:

  • HO must be localized in placental tissue,

  • HO

Carbon monoxide

Attention has focused on the vascular effects of CO in the placenta. It has been noted that at term arterial vessels of the feto-placental circulation are maintained in a state of near-maximal dilation in order to facilitate oxygen and nutrient delivery [37]. The placenta lacks innervation [38] and therefore is reliant solely upon locally produced and circulating vasoactive compounds for hemodynamic control. With the abundance of HO protein found throughout the human placenta, coupled with the

The antioxidant capabilities of biliverdin/bilirubin

The placenta is a site of increased oxidative stress as cells of fetal origin (trophoblast cells) are in direct communication with the highly oxygenated maternal circulation. The growing fetus is susceptible to increased levels of oxidative stress as most reactive oxygen species are membrane permeable and are capable of crossing the placenta [52]. In addition, while total lipids in the fetal circulation are lower than that of an adult, a higher proportion of polyunsaturated fatty acids has been

Heme oxygenase and preeclampsia

Heme oxygenase and its catalytic products may play a significant role in the progression of a healthy pregnancy to term. With this enzyme being linked to several vital tasks of pregnancy such as placentation, placental hemodynamic control, and antioxidant protection, it is no surprise that the activity or dysfunction of this enzyme is under investigation in several disorders of pregnancy. In this review, the role of HO in the pathophysiology of preeclampsia (PET) will be highlighted as it has

Targeting the heme oxygenase signaling pathway therapeutically

Preeclampsia remains one of the leading causes of maternal and fetal/neonatal morbidity and mortality worldwide [61]; currently no therapeutic intervention to prevent or attenuate the disease process is known. The epidemiological studies showing that women who smoke cigarettes have a 33% reduced risk of developing PET [79] provides supporting evidence for the role that the HO-CO system may play in the development of this disorder and a direction for therapeutic development [80]. A recent study

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    Sources of financial support: Strategic Training Initiative in Research in Reproductive Health Sciences (STIRRHS), CIHR.

    ☆☆

    This article is part of a series of reviews on “Heme oxygenase in human disease.” The full list of papers may be found on the home page of the journal.

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