Heme Oxygenases in Pregnancy II: HO‐2 is Downregulated in Human Pathologic Pregnancies

Zenclussen, Ana Claudia; Lim, Eunji; Knoeller, S.; Knackstedt, M.; Hertwig, K; Hagen, Edward H.; Klapp, Burghard F.; Arck, PC

doi:10.1034/j.1600-0897.2003.00047.x

Cited by 80 publications

(68 citation statements)

References 61 publications

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“…These data on up-regulated HO-1 after Co-PP treatment nicely support findings from other groups in transplanted organs (16). HO-2 was not found to be up-regulated after Co-PP in other tissues; however, we already reported that HO-2 can be up-or down-regulated at the fetal-maternal interface (9,10,18). These data on augmented HO-2 protein expression at the fetal-maternal interface suggest that HO-2 is being differently regulated at the fetal-maternal interface than in other tissues.…”

Section: Co-pp Application Up-regulated Ho-1 Expression At the Fetalmsupporting

confidence: 78%

“…Furthermore, boosting abortion with sonic stress or IL-12 application down-regulated the HO-1 and HO-2 expression at the murine fetal-maternal interface (9). Interestingly, HO-1 and HO-2 were also down-regulated at the fetal maternal interface from patients undergoing spontaneous abortion during the first trimester, as compared with age-matched women undergoing normal pregnancies (18).…”

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confidence: 96%

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Protection from Abortion by Heme Oxygenase-1 Up-Regulation Is Associated with Increased Levels of Bag-1 and Neuropilin-1 at the Fetal-Maternal Interface

Sollwedel

Bertoja

Zenclussen

et al. 2005

The Journal of Immunology

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Tolerance mechanisms allowing pregnancy success resemble those involved in allograft acceptance. Heme oxygenase (HO) is a tissue-protective molecule, which allows graft acceptance and is known to have antiapoptotic effects on several cell types. We previously reported down-regulated levels of HO-1 and HO-2 in placenta from allopregnant mice undergoing abortion. In this study, we analyzed whether the up-regulation of HO-1 by cobalt-protoporphyrin (Co-PP) during implantation window can rescue mice from abortion. Induction of HO-1 by Co-PP treatment prevented fetal rejection, whereas the down-regulation of HOs by zinc-protoporphyrin application boosted abortion. The beneficial effect of HO-1 induction was not related to a local shift to Th2-profile or to a change in the NO system. Interestingly, the expression of the antiapoptotic/cytoprotective molecule Bag-1 as well as the levels of neuropilin-1, a novel marker for T regulatory cells, were up-regulated after Co-PP treatment. Our data strongly support a very important role for HO-1 in fetal allotolerance and suggest that HO-1 might be protective by up-regulating tissue protective molecules, i.e., Bag-1, and by activating T regulatory cells rather than by changing the local cytokine profile.

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Section: Co-pp Application Up-regulated Ho-1 Expression At the Fetalmsupporting

confidence: 78%

mentioning

confidence: 96%

Protection from Abortion by Heme Oxygenase-1 Up-Regulation Is Associated with Increased Levels of Bag-1 and Neuropilin-1 at the Fetal-Maternal Interface

Sollwedel

Bertoja

Zenclussen

et al. 2005

The Journal of Immunology

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“…This is strongly supported by the demonstration that biliverdin administration rescued the impaired inflammatory and reparative response of the HO-2-null mice; it accelerated wound repair, promoted resolution, and attenuated neovascularization. It is noteworthy that HO-2 expression levels have been shown to decrease significantly in human pathologies and conditions that are associated with chronic inflammation such as preeclamptic pregnancies 5,50 and prolonged cigarette smoking. 6 Hence, it is not unreasonable to speculate that there is a causal relationship between the levels of HO-2 expression and activity and unresolved chronic inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…HO-1 is an inducible enzyme, whereas HO-2 displays, in general, a constitutive expression that is developmentally regulated 4 and is altered in human pathological conditions. 5,6 HO-1 and HO-2 are alike in terms of mechanisms of heme oxidation, co-factor and substrate specificity, and susceptibility to inhibition by porphyrins. 2,7 They differ in their postulated function: whereas HO-2 is believed to function as the constitutive HO activity contributing to cell homeostasis, HO-1 expression is relatively low in most tissues, and its significance comes to light in response to injury.…”

mentioning

confidence: 99%

Heme Oxygenase-2 Is a Critical Determinant for Execution of an Acute Inflammatory and Reparative Response

Seta

Bellner

Rezzani

et al. 2006

The American Journal of Pathology

120

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Heme oxygenase (HO) represents an intrinsic antiinflammatory system based on its ability to regulate leukocyte function and inhibit expression of proinflammatory cytokines. This anti-inflammatory function is linked to the inducible isoform HO-1; the role of the constitutive isoform HO-2 is unknown. The current study was undertaken to investigate the role of HO-2 in the regulation of the acute inflammatory and reparative response by using HO-2-null mice and well-established animal models of epithelial injury and antigen-induced peritonitis. Here we show that in vivo deletion of HO-2 disables execution of the acute inflammatory and reparative response after epithelial injury and leads to an exaggerated inflammatory response in antigen-induced peritonitis. HO-2 deletion was associated with impaired HO-1 induction, indicating that HO-2 is critical for HO-1 expression and that the subsequent failure to up-regulate the HO system may contribute to unresolved inflammation and the development of chronic inflammatory conditions. Indeed, supplementation with the HO bioactive product, biliverdin, rescued the acute inflammatory and reparative response in HO-2-null mice. Thus, HO-2 sets in place a basal tone of anti-inflammatory signals that may be a prerequisite for the ordered execution of an inflammatory and reparative response.

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“…Importantly, HO-2 expression is decreased in endothelial cells from preeclamptic and fetal growth-restricted placentas (4). Lastly, HO-2 expression is decreased in synctiotrophoblasts and invasive trophoblasts from third-trimester preeclamptic patients (29). These seminal studies illustrate that HO-2, the constitutively expressed enzyme, may play a role in the pathophysiology of preeclampsia.…”

Section: Discussionmentioning

confidence: 95%

Heme oxygenase-1 promotes migration and β-epithelial Na⁺ channel expression in cytotrophoblasts and ischemic placentas

Warrington

Coleman

Skaggs

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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oxygenase-1 promotes migration and ␤-epithelial Na ϩ channel expression in cytotrophoblasts and ischemic placentas. Am J Physiol Regul Integr Comp Physiol 306: R641-R646, 2014. First published February 19, 2014 doi:10.1152/ajpregu.00566.2013.-Preeclampsia is thought to arise from inadequate cytotrophoblast migration and invasion of the maternal spiral arteries, resulting in placental ischemia and hypertension. Evidence suggests that altered expression of epithelial Na ϩ channel (ENaC) proteins may be a contributing mechanism for impaired cytotrophoblast migration. ENaC activity is required for normal cytotrophoblast migration. Moreover, ␤-ENaC, the most robustly expressed placental ENaC message, is reduced in placentas from preeclamptic women. We recently demonstrated that heme oxygenase-1 (HO-1) protects against hypertension in a rat model of placental ischemia; however, whether HO-1 regulation of ␤-ENaC contributes to the beneficial effects of HO-1 is unknown. The purpose of this study was to determine whether ␤-ENaC mediates cytotrophoblast migration and whether HO-1 enhances ENaC-mediated migration. We showed that placental ischemia, induced by reducing uterine perfusion suppressed, and HO-1 induction restored, ␤-ENaC expression in ischemic placentas. Using an in vitro model, we found that HO-1 induction, using cobalt protoporphyrin, stimulates cytotrophoblast ␤-ENaC expression by 1.5-and 1.8-fold (10 and 50 M). We then showed that silencing of ␤-ENaC in cultured cytotrophoblasts (BeWo cells), by expression of dominant-negative constructs, reduced migration to 56 Ϯ 13% (P Ͻ 0.05) of control. Importantly, HO-1 induction enhanced migration (43 Ϯ 5% of control, P Ͻ 0.05), but the enhanced migratory response was entirely blocked by ENaC inhibition with amiloride (10 M). Taken together, our results suggest that ␤-ENaC mediates cytotrophoblast migration and increasing ␤-ENaC expression by HO-1 induction enhances migration. HO-1 regulation of cytotrophoblast ␤-ENaC expression and migration may be a potential therapeutic target in preeclamptic patients. cytotrophoblast; preeclampsia; heme oxygenase-1; placenta; ␤-ENaC PREECLAMPSIA IS A PREGNANCY-SPECIFIC condition characterized by hypertension, proteinuria, and maternal vascular dysfunction. It is the leading cause of maternal and perinatal mortality and morbidity. Currently, there are no effective preventive and treatment strategies except for the early delivery of the placenta and fetus. Because the symptoms of preeclampsia remit after delivery, the placenta has been implicated as the major contributor to the pathophysiology of the disorder. The prevailing hypothesis is that preeclampsia is initiated by abnormal cytotrophoblast migration and subsequent invasion of the maternal uterine spiral arteries, resulting in restricted blood flow to the developing uteroplacental unit and placental ischemia.

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Heme Oxygenases in Pregnancy II: HO‐2 is Downregulated in Human Pathologic Pregnancies

Cited by 80 publications

References 61 publications

Protection from Abortion by Heme Oxygenase-1 Up-Regulation Is Associated with Increased Levels of Bag-1 and Neuropilin-1 at the Fetal-Maternal Interface

Protection from Abortion by Heme Oxygenase-1 Up-Regulation Is Associated with Increased Levels of Bag-1 and Neuropilin-1 at the Fetal-Maternal Interface

Heme Oxygenase-2 Is a Critical Determinant for Execution of an Acute Inflammatory and Reparative Response

Heme oxygenase-1 promotes migration and β-epithelial Na⁺ channel expression in cytotrophoblasts and ischemic placentas

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Heme Oxygenases in Pregnancy II: HO‐2 is Downregulated in Human Pathologic Pregnancies

Cited by 80 publications

References 61 publications

Protection from Abortion by Heme Oxygenase-1 Up-Regulation Is Associated with Increased Levels of Bag-1 and Neuropilin-1 at the Fetal-Maternal Interface

Protection from Abortion by Heme Oxygenase-1 Up-Regulation Is Associated with Increased Levels of Bag-1 and Neuropilin-1 at the Fetal-Maternal Interface

Heme Oxygenase-2 Is a Critical Determinant for Execution of an Acute Inflammatory and Reparative Response

Heme oxygenase-1 promotes migration and β-epithelial Na+ channel expression in cytotrophoblasts and ischemic placentas

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Heme oxygenase-1 promotes migration and β-epithelial Na⁺ channel expression in cytotrophoblasts and ischemic placentas