Heme Oxygenase System Research Articles

The clinical relevance of heme detoxification by the macrophage heme oxygenase system.

Heme degradation by the heme oxygenase (HMOX) family of enzymes is critical for maintaining homeostasis and limiting heme-induced tissue damage. Macrophages express HMOX1 and 2 and are critical sites of heme degradation in healthy and diseased states. Here we review the functions of the macrophage heme oxygenase system and its clinical relevance in discrete groups of pathologies where heme has been demonstrated to play a driving role. HMOX1 function in macrophages is essential for limiting oxidative tissue damage in both acute and chronic hemolytic disorders. By degrading pro-inflammatory heme and releasing anti-inflammatory molecules such as carbon monoxide, HMOX1 fine-tunes the acute inflammatory response with consequences for disorders of hyperinflammation such as sepsis. We then discuss divergent beneficial and pathological roles for HMOX1 in disorders such as atherosclerosis and metabolic syndrome, where activation of the HMOX system sits at the crossroads of chronic low-grade inflammation and oxidative stress. Finally, we highlight the emerging role for HMOX1 in regulating macrophage cell death via the iron- and oxidation-dependent form of cell death, ferroptosis. In summary, the importance of heme clearance by macrophages is an active area of investigation with relevance for therapeutic intervention in a diverse array of human diseases.

Exploring the pathophysiological influence of heme oxygenase-1 on neuroinflammation and depression: A study of phytotherapeutic-based modulation

BackgroundThe heme oxygenase (HO) system plays a significant role in neuroprotection and reduction of neuroinflammation and neurodegeneration. The system, via isoforms HO-1 and HO-2, regulates cellular redox balance. HO-1, an antioxidant defense enzyme, is highlighted due to its association with depression, characterized by heightened neuroinflammation and impaired oxidative stress responses. MethodologyWe observed the pathophysiology of HO-1 and phytochemicals as its modulator. We explored Science Direct, Scopus, and PubMed for a comprehensive literature review. Bibliometric and temporal trend analysis were done using VOSviewer. ResultsSeveral phytochemicals can potentially alleviate neuroinflammation and oxidative stress-induced depressive symptoms. These effects result from inhibiting the MAPK and NK-κB pathways - both implicated in the overproduction of pro-inflammatory factors - and from the upregulation of HO-1 expression mediated by Nrf2. Bibliometric and temporal trend analysis further validates these associations. ConclusionIn summary, our findings suggest that antidepressant agents can mitigate neuroinflammation and depressive disorder pathogenesis via the upregulation of HO-1 expression. These agents suppress pro-inflammatory mediators and depressive-like symptoms, demonstrating that HO-1 plays a significant role in the neuroinflammatory process and the development of depression.

Evaluation of the value of exhaled carbon monoxide in the differentiation of viral and bacterial pneumonia.

Aim: This study compared exhaled carbon monoxide (CO) levels in patients hospitalized for bacterial and COVID-19-related viral community-acquired pneumonia. Materials & methods: The study included a total of 150 patients: 50 patients hospitalized for COVID-19 between February 2021 and March 2022, 50 patients with bacterial community-acquired pneumonia and 50 healthy controls. Results: In comparisons of exhaled CO levels among the groups, there was no significant difference between patients with bacterial pneumonia and controls, whereas patients with COVID-19 pneumonia had significantly higher exhaled CO levels compared with both the bacterial pneumonia and control groups (p<0.001). Conclusion: Viral agents can directly affect the heme oxygenase system of the lower respiratory tract, leading to greater increases in ferritin and exhaled CO levels compared with bacterial pneumonia.

Resveratrol as a Promising Polyphenol in Age-Associated Cardiac Alterations.

According to a widely accepted theory, oxidative stress is considered to be the number one trigger of aging-associated degenerative processes including cardiovascular diseases. In the context of aging-research, resveratrol receives special attention with its surprising number of health benefits. The aim of our study was to examine the anti-inflammatory and antioxidant effects of this dietary polyphenol in aging rat heart. 20-month-old female and male Wistar rats were divided into control (untreated) and resveratrol-treated groups. Resveratrol was administered at a dose of 0.05 mg/ml for 12 weeks dissolved in drinking water, while the control rats received ad libitum water. Cardiac level of reactive oxygen species (ROS), nuclear factor kappa B (NFκB), tumor necrosis factor alpha (TNF-α), and glutathione (GSH) parameters, as well as the activity of myeloperoxidase (MPO) and heme oxygenase (HO) enzymes were detected. Together with the biochemical measurements, hearts were isolated and used for an exposure of ischemic-reperfusion injury via Langendorff perfusion system. 12 week of resveratrol treatment suppressed the age-related inflammatory pathways including the expression of TNF-α, NFκB, and the activity of MPO while intensified the endogenous antioxidant defenses through the induction of GSH and HO system. Presumably, as a result of these processes, the necrotic area of the heart in response to an acute injury was also significantly reduced in the resveratrol-treated groups. Our findings confirmed that resveratrol has cardioprotective effects at several points by counteracting the aging-associated cellular malfunctions in the heart.

Roles of Heme Oxygenase-1 in Neuroinflammation and Brain Disorders

The heme oxygenase (HO) system is believed to be a crucial mechanism for the nervous system under stress conditions. HO degrades heme to carbon monoxide, iron, and biliverdin. These heme degradation products are involved in modulating cellular redox homeostasis. The first identified isoform of the HO system, HO-1, is an inducible protein that is highly expressed in peripheral organs and barely detectable in the brain under normal conditions, whereas HO-2 is a constitutive protein that is highly expressed in the brain. Several lines of evidence indicate that HO-1 dysregulation is associated with brain inflammation and neurodegeneration, including Parkinson’s and Alzheimer’s diseases. In this review, we summarize the essential roles that the HO system plays in ensuring brain health and the molecular mechanism through which HO-1 dysfunction leads to neurodegenerative diseases and disruption of nervous system homeostasis. We also provide a summary of the herbal medicines involved in the regulation of HO-1 expression and explore the current situation regarding herbal remedies and brain disorders.

Heme oxygenase-1 & 2 and their potential contribution in heme induced colorectal carcinogenesis

BackgroundLiterature suggests Heme oxygenase (HO) system to be a double-edged sword which can promote both cytoprotection as well as carcinogenicity. The aim of this study was to investigate the role of heme in HO-1 and HO-2 induced colorectal carcinogenesis and the clinicopathological significance of their expressions in patients with colorectal carcinoma (CRC). MethodsHO-1 and HO-2 expression alterations in normal colonic epithelial (FHC) and colon cancer cells (SW480) were explored following treatment with 0 µM, 25 µM, 100 µM and 250 µM concentrations of hemin, using qPCR. Fifty paired CRC and adjacent non-neoplastic samples were subjected to qPCR to determine the HO-1 and HO-2 expression. Clinicopathological associations of HO-1 and HO-2 expression levels were determined. ResultsLow concentrations of hemin caused upregulation and high concentration caused downregulation of HO-1 expression, whereas HO-2 expression was significantly downregulated with all hemin concentrations in FHC. HO-1 expression in SW480 was increased with all hemin concentrations and HO-2 expression was downregulated at the highest hemin concentration. HO-1 and HO-2 expressions in adjacent non-neoplastic tissue was significantly higher than that of CRC. Expression of HO-1 was significantly higher than HO-2, in both CRC and adjacent non-neoplastic tissue. Sex, HFE expression and lymph-vascular invasion were significantly correlated with HO-1 expression. HO-2 expression showed significant associations with staging, local spread and recurrence of tumour. ConclusionHO-1 and HO-2 expression is respectively induced and repressed by exogenous hemin in normal colon and colon cancer cells. HO-1 and HO-2 expression profiles in CRC are correlated with the assessed clinicopathological features of CRC, suggesting the possible implications of HO expression status in CRC pathogenesis.

Potential Implications of Rimonabant on Age-Related Oxidative Stress and Inflammation.

Over the last decades, growing interest has turned to preventive and therapeutic approaches for achieving successful aging. Oxidative stress and inflammation are fundamental features of cardiovascular diseases; therefore, potential targets of them can improve cardiac outcomes. Our study aimed to examine the involvement of the endocannabinoid system, especially the CB1 receptor blockade, on inflammatory and oxidant/antioxidant processes. Twenty-month-old female and male Wistar rats were divided into rimonabant-treated and aging control (untreated) groups. Rimonabant, a selective CB1 receptor antagonist, was administered at the dose of 1 mg/kg/day intraperitoneally for 2 weeks. Cardiac amounts of ROS, the antioxidant glutathione and superoxide dismutase (SOD), and the activity and concentration of the heme oxygenase (HO) enzyme were detected. Among inflammatory parameters, nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and myeloperoxidase (MPO) enzyme activity were measured. Two weeks of low dose rimonabant treatment significantly reduced the cardiac ROS via boosting of the antioxidant defense mechanisms as regards the HO system, and the SOD and glutathione content. Consistently, the age-related inflammatory response was alleviated. Rimonabant-treated animals showed significantly decreased NF-κB, TNF-α, and MPO levels. Our findings prove the beneficial involvement of CB1 receptor blocker rimonabant on inflammatory and oxidative damages to the aging heart.

Hemin-induced increase in saponin content contributes to the alleviation of osmotic and cold stress damage to Conyza blinii in a heme oxygenase 1-dependent manner.

Hemin can improve the stress resistance of plants through the heme oxygenase system. Additionally, substances contained in plants, such as secondary metabolites, can improve stress resistance. However, few studies have explored the effects of hemin on secondary metabolite content. Therefore, the effects of hemin on saponin synthesis and the mechanism of plant injury relief by hemin in Conyza blinii were investigated in this study. Hemin treatment promoted plant growth and increased the antioxidant enzyme activity and saponin content of C. blinii under osmotic stress and cold stress. Further study showed that hemin could provide sufficient precursors for saponin synthesis by improving the photosynthetic capacity of C. blinii and increasing the gene expression of key enzymes in the saponin synthesis pathway, thus increasing the saponin content. Moreover, the promotion effect of hemin on saponin synthesis is dependent on heme oxygenase-1 and can be reversed by the inhibitor Zn-protoporphyrin-IX (ZnPPIX). This study revealed that hemin can increase the saponin content of C. blinii and alleviate the damage caused by abiotic stress, and it also broadened the understanding of the relationship between hemin and secondary metabolites in plant abiotic stress relief.

Tin Mesoporphyrin Selectively Reduces Non-Small-Cell Lung Cancer Cell Line A549 Proliferation by Interfering with Heme Oxygenase and Glutathione Systems.

In order to maintain redox homeostasis, non-small-cell lung cancer (NSCLC) increases the activation of many antioxidant systems, including the heme-oxygenase (HO) system. The overexpression of HO-1 has been often associated with chemoresistance and tumor aggressiveness. Our results clearly showed an overexpression of the HO-1 protein in A549 NSCLC cell lines compared to that in non-cancerous cells. Thus, we hypothesized that “off-label” use of tin mesoporphyrin, a well-known HO activity inhibitor clinically used for neonatal hyperbilirubinemia, has potential use as an anti-cancer agent. The pharmacological inhibition of HO activity caused a reduction in cell proliferation and migration of A549. SnMP treatment caused an increase in oxidative stress, as demonstrated by the upregulation of reactive oxygen species (ROS) and the depletion of glutathione (GSH) content. To support these data, Western blot analysis was performed to analyze glucose-6-phosphate dehydrogenase (G6PD), TP53-induced glycolysis and the apoptosis regulator (TIGAR), and the glutamate cysteine ligase catalytic (GCLC) subunit, as they represent the main regulators of the pentose phosphate pathway (PPP) and glutathione synthesis, respectively. NCI-H292, a subtype of the NSCLC cell line, did not respond to SnMP treatment, possibly due to low basal levels of HO-1, suggesting a cellular-dependent antitumorigenic effect. Altogether, our results suggest HO activity inhibition may represent a potential target for selective chemotherapy in lung cancer subtypes.

Significance of Heme and Heme Degradation in the Pathogenesis of Acute Lung and Inflammatory Disorders

The heme molecule serves as an essential prosthetic group for oxygen transport and storage proteins, as well for cellular metabolic enzyme activities, including those involved in mitochondrial respiration, xenobiotic metabolism, and antioxidant responses. Dysfunction in both heme synthesis and degradation pathways can promote human disease. Heme is a pro-oxidant via iron catalysis that can induce cytotoxicity and injury to the vascular endothelium. Additionally, heme can modulate inflammatory and immune system functions. Thus, the synthesis, utilization and turnover of heme are by necessity tightly regulated. The microsomal heme oxygenase (HO) system degrades heme to carbon monoxide (CO), iron, and biliverdin-IXα, that latter which is converted to bilirubin-IXα by biliverdin reductase. Heme degradation by heme oxygenase-1 (HO-1) is linked to cytoprotection via heme removal, as well as by activity-dependent end-product generation (i.e., bile pigments and CO), and other potential mechanisms. Therapeutic strategies targeting the heme/HO-1 pathway, including therapeutic modulation of heme levels, elevation (or inhibition) of HO-1 protein and activity, and application of CO donor compounds or gas show potential in inflammatory conditions including sepsis and pulmonary diseases.

Heme Oxygenase 1: A Defensive Mediator in Kidney Diseases.

The incidence of kidney disease is rising, constituting a significant burden on the healthcare system and making identification of new therapeutic targets increasingly urgent. The heme oxygenase (HO) system performs an important function in the regulation of oxidative stress and inflammation and, via these mechanisms, is thought to play a role in the prevention of non-specific injuries following acute renal failure or resulting from chronic kidney disease. The expression of HO-1 is strongly inducible by a wide range of stimuli in the kidney, consequent to the kidney’s filtration role which means HO-1 is exposed to a wide range of endogenous and exogenous molecules, and it has been shown to be protective in a variety of nephropathological animal models. Interestingly, the positive effect of HO-1 occurs in both hemolysis- and rhabdomyolysis-dominated diseases, where the kidney is extensively exposed to heme (a major HO-1 inducer), as well as in non-heme-dependent diseases such as hypertension, diabetic nephropathy or progression to end-stage renal disease. This highlights the complexity of HO-1’s functions, which is also illustrated by the fact that, despite the abundance of preclinical data, no drug targeting HO-1 has so far been translated into clinical use. The objective of this review is to assess current knowledge relating HO-1’s role in the kidney and its potential interest as a nephroprotection agent. The potential therapeutic openings will be presented, in particular through the identification of clinical trials targeting this enzyme or its products.

Immune Modulation by Inhibitors of the HO System.

The heme oxygenase (HO) system involves three isoforms of this enzyme, HO-1, HO-2, and HO-3. The three of them display the same catalytic activity, oxidating the heme group to produce biliverdin, ferrous iron, and carbon monoxide (CO). HO-1 is the isoform most widely studied in proinflammatory diseases because treatments that overexpress this enzyme promote the generation of anti-inflammatory products. However, neonatal jaundice (hyperbilirubinemia) derived from HO overexpression led to the development of inhibitors, such as those based on metaloproto- and meso-porphyrins inhibitors with competitive activity. Further, non-competitive inhibitors have also been identified, such as synthetic and natural imidazole-dioxolane-based, small synthetic molecules, inhibitors of the enzyme regulation pathway, and genetic engineering using iRNA or CRISPR cas9. Despite most of the applications of the HO inhibitors being related to metabolic diseases, the beneficial effects of these molecules in immune-mediated diseases have also emerged. Different medical implications, including cancer, Alzheimer´s disease, and infections, are discussed in this article and as to how the selective inhibition of HO isoforms may contribute to the treatment of these ailments.

Therapeutic Potential of Carbon Monoxide (CO) and Hydrogen Sulfide (H2S) in Hemolytic and Hemorrhagic Vascular Disorders-Interaction between the Heme Oxygenase and H2S-Producing Systems.

Over the past decades, substantial work has established that hemoglobin oxidation and heme release play a pivotal role in hemolytic/hemorrhagic disorders. Recent reports have shown that oxidized hemoglobins, globin-derived peptides, and heme trigger diverse biological responses, such as toll-like receptor 4 activation with inflammatory response, reprogramming of cellular metabolism, differentiation, stress, and even death. Here, we discuss these cellular responses with particular focus on their mechanisms that are linked to the pathological consequences of hemorrhage and hemolysis. In recent years, endogenous gasotransmitters, such as carbon monoxide (CO) and hydrogen sulfide (H2S), have gained a lot of interest in connection with various human pathologies. Thus, many CO and H2S-releasing molecules have been developed and applied in various human disorders, including hemolytic and hemorrhagic diseases. Here, we discuss our current understanding of oxidized hemoglobin and heme-induced cell and tissue damage with particular focus on inflammation, cellular metabolism and differentiation, and endoplasmic reticulum stress in hemolytic/hemorrhagic human diseases, and the potential beneficial role of CO and H2S in these pathologies. More detailed mechanistic insights into the complex pathology of hemolytic/hemorrhagic diseases through heme oxygenase-1/CO as well as H2S pathways would reveal new therapeutic approaches that can be exploited for clinical benefit.

A Potential Involvement of Anandamide in the Modulation of HO/NOS Systems: Women, Menopause, and "Medical Cannabinoids".

Endocannabinoids and their receptors are present in the cardiovascular system; however, their actions under different pathological conditions remain controversial. The aim of our study was to examine the effects of anandamide (AEA) on heme oxygenase (HO) and nitric oxide synthase (NOS) systems in an estrogen-depleted rat model. Sham-operated (SO) and surgically induced estrogen-deficient (OVX) female Wistar rats were used. During a two-week period, a group of OVX rats received 0.1 mg/kg estrogen (E2) per os, while AEA-induced alterations were analyzed after two weeks of AEA treatment at the dose of 1.0 mg/kg. At the end of the experiment, cardiac activity and expression of HO and NOS enzymes, content of cannabinoid 1 receptor, as well as concentrations of transient potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) were measured. Our results show that estrogen withdrawal caused a significant decrease in both NOS and HO systems, and a similar tendency was observed regarding the TRPV1/CGRP pathway. Two weeks of either AEA or E2 treatment restored the adverse changes; however, the combined administration of these two molecules did not result in a further improvement. In light of the potential relationship between AEA and HO/NOS systems, AEA-induced upregulation of HO/NOS enzymes may be a therapeutic strategy in estrogen-deficient conditions.

P0916OLIVE LEAF EXTRACT IMPROVES RENAL ANTIOXIDANT DEFENSE WITHOUT ALTERING THE HEME OXYGENASE-1/BILIVERDIN REDUCTASE PATHWAY IN HYPERTENSIVE RATS WITH FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Abstract Background and Aims Oxidative stress is implicated in the pathophysiology of chronic kidney disease. Previously, we showed that adriamycin (anticancer agent, enhances reactive oxygen species production) induced focal segmental glomerular sclerosis (FSGS) with massive proteinuria in spontaneously hypertensive rats (SHR). The heme oxygenase (HO) system plays an important role in regulating oxidative stress and is protective in chronic kidney disease. HO-1 is a cytoprotective enzyme that catalyzes the conversion of highly reactive free heme molecules into biliverdin, carbon monoxide, and iron. Biliverdin is subsequently converted to bilirubin by biliverdin reductase and has potent antioxidant effect. Olive leaf extract (OLE, Olea europaea L.) is rich in phenolic compounds that are known to possess powerful antioxidant properties. Here, we aimed to investigate the effects of OLE, focusing on its modulatory role on oxidative stress and HO-1/BVR pathway in the kidney of SHR with adriamycin-induced FSGS. Method Adult females SHR were divided into three groups. Control rats received vehicle. Two other groups, FSGS and FSGS+OLE, received adriamycin (2 mg/kg body weight i.v.) twice in 3-week-interval. After the second injection, FSGS+OLE group received OLE (80 mg/kg/day) by gavage for 6 weeks. Mean blood pressure (MAP), urine albumin-to-creatinine (Ualb/cr), renal HO-1 and biliverdin reductase protein expressions (Western Blot), protein carbonyl content (PCOs), and antioxidant capacity (ABTS) were analyzed. Results In FSGS group albuminuria was significantly increased in comparison to the level in control. Chronic consumption of OLE markedly, but not significantly decreased Ualb/cr compared to that in control. Analysis of renal PCOs revealed that significant enhancement of protein oxidation in the kidney of model group was reduced after OLE treatment to the level as in control. The ABTS level in kidney homogenates significantly decreased in FSGS group in comparison to the level in control. OLE significantly increased renal antioxidant capacity in FSGS+OLE group compared to that in model group. Western blot analysis of HO-1, and biliverdin reductase in the kidney revealed that protein expressions of both enzymes were significantly decreased in FSGS group compared to that in control. Following OLE treatment in FSGS+OLE group protein expressions of HO-1, and biliverdin reductase remained at similar level as in model group. No change in MAP values were observed between control and model groups. OLE significantly decreased MAP in FSGS+OLE group in comparison to the value of model group, and nearly significant reduction of MAP compared to the value of control. Conclusion Collectively, our results showed that OLE expressed its antioxidant property and improved oxidative status in the kidney of SHR with ADR-induced FSGS, independently of the HO-1/BVR pathway.

Cannabidiol Protects Dopaminergic Neurons in Mesencephalic Cultures against the Complex I Inhibitor Rotenone Via Modulation of Heme Oxygenase Activity and Bilirubin.

Phytocannabinoids protect neurons against stressful conditions, possibly via the heme oxygenase (HO) system. In cultures of primary mesencephalic neurons and neuroblastoma cells, we determined the capability of cannabidiol (CBD) and tetrahydrocannabinol (THC) to counteract effects elicited by complex I-inhibitor rotenone by analyzing neuron viability, morphology, gene expression of IL6, CHOP, XBP1, HO-1 (stress response), and HO-2, and in vitro HO activity. Incubation with rotenone led to a moderate stress response but massive degeneration of dopaminergic neurons (DN) in primary mesencephalic cultures. Both phytocannabinoids inhibited in-vitro HO activity, with CBD being more potent. Inhibition of the enzyme reaction was not restricted to neuronal cells and occurred in a non-competitive manner. Although CBD itself decreased viability of the DNs (from 100 to 78%), in combination with rotenone, it moderately increased survival from 28.6 to 42.4%. When the heme degradation product bilirubin (BR) was added together with CBD, rotenone-mediated degeneration of DN was completely abolished, resulting in approximately the number of DN determined with CBD alone (77.5%). Using N18TG2 neuroblastoma cells, we explored the neuroprotective mechanism underlying the combined action of CBD and BR. CBD triggered the expression of HO-1 and other cell stress markers. Co-treatment with rotenone resulted in the super-induction of HO-1 and an increased in-vitro HO-activity. Co-application of BR completely mitigated the rotenone-induced stress response. Our findings indicate that CBD induces HO-1 and increases the cellular capacity to convert heme when stressful conditions are met. Our data further suggest that CBD via HO may confer full protection against (oxidative) stress when endogenous levels of BR are sufficiently high.

Possible role of garlic oil in ameliorating renal injury after liver ischemia/reperfusion in rats.

Acute liver failure induces renal injury by triggering inflammation and oxidative stress. The heme oxygenase system has a preventive role against reperfusion injury, while garlic oil has antioxidants and anti-inflammatory effects. This study investigated the protective effects of garlic oil pretreatment on remote renal functions after liver ischemia/reperfusion (I/R), and clarifying gene expressions of heme oxygenase 1 (HO1), autophagy-related 7 (Atg7) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) in renal tissues. Thirty six adult female Wistar rats were randomly divided into control, garlic oil-supplemented, liver I/R, and garlic oil-pretreated liver I/R groups. Liver ischemia was performed in anesthetized rats for 45 min, followed by reperfusion for 24 hours in metabolic cages. Serum samples were used for determination of liver enzymes and creatinine levels and total antioxidant capacity (TAC). Urine samples were assayed for albumin, volume and creatinine concentration. Right liver lobe and right kidney specimens were used for determination of oxidative stress markers (colorimeterically). Also, gene expressions of HO1, Atg7 and PGC1α were investigated in right kidney specimens using real time PCR. Left kidney specimens were used for histopathological studies. Liver I/R group exhibited higher liver enzymes and creatinine levels in serum, prominent oxidative stress in both liver and renal tissues, albuminuria, lowered GFR deranged renal structure, and upregulated HO1, Atg7 and PGC1α gene expressions in renal tissues. Garlic oil-pretreated I/R group restricted such detrimental changes in renal functions and structure, though it caused further upregulation of the studied gene expression in renal tissue to alleviate the oxidative stress. It is concluded that garlic oil exerted reno-protective effected against remote organ damage induced by liver I/R injury, through enhancing HO1, Atg7 and PGC1α gene expressions.

Trophoblast-induced spiral artery remodelling and uteroplacental haemodynamics in pregnant rats with increased blood pressure induced by heme oxygenase inhibition

IntroductionThe aim of the present study was to determine the contribution of the heme oxygenase (HO) system to the adaptation of the uteroplacental circulation to pregnancy in the rat, and its relationship with the maintenance of blood pressure during late gestation. MethodsThe HO inhibitor, stannous mesoporphyrin (SnMP), or vehicle were administered intraperitoneally to virgin and midpregnant rats. Mean arterial pressure (MAP) was measured before and after the treatment, in the conscious rats. Uterine and radial arteries blood flow velocities were obtained from pregnant rats at days 14 and 19 of gestation using high frequency ultrasonography. Trophoblast invasion and spiral arteries remodelling were analyzed in the mesometrial triangle of pregnant rats by immunohistochemistry. ResultsHO activity inhibition during late gestation induced a significantly increase in the MAP of pregnant rats (114 ± 1 mmHg vs 100 ± 2 mmHg, p < 0.05) but it did not affect this parameter in virgin rats (121 ± 2 mmHg vs 124 ± 3 mmHg). MAP elevation was associated with marked (p < 0.05) decreases in the systolic and diastolic flow velocities in uterine and radial arteries, as compared with pregnant control rats. Furthermore, spiral arteries of pregnant rats treated with SnMP showed lower (p < 0.001) proportion of lumen circumference covered by trophoblast (21 ± 3%) and a higher (p < 0.05) proportion of vascular smooth muscle (33 ± 5%) than control pregnant rats (59 ± 5% and 16 ± 5%, respectively) DiscussionThese data indicate that HO system play an important role in the adaptation of the uteroplacental circulation to pregnancy and in the blood pressure regulation during late gestation.

Role of Heme Oxygenase as a Modulator of Heme-Mediated Pathways

The heme oxygenase (HO) system is essential for heme and iron homeostasis and necessary for adaptation to cell stress. HO degrades heme to biliverdin (BV), carbon monoxide (CO) and ferrous iron. Although mostly beneficial, the HO reaction can also produce deleterious effects, predominantly attributed to excessive product formation. Underrated so far is, however, that HO may exert effects additionally via modulation of the cellular heme levels. Heme, besides being an often-quoted generator of oxidative stress, plays also an important role as a signaling molecule. Heme controls the anti-oxidative defense, circadian rhythms, activity of ion channels, glucose utilization, erythropoiesis, and macrophage function. This broad spectrum of effects depends on its interaction with proteins ranging from transcription factors to enzymes. In degrading heme, HO has the potential to exert effects also via modulation of heme-mediated pathways. In this review, we will discuss the multitude of pathways regulated by heme to enlarge the view on HO and its role in cell physiology. We will further highlight the contribution of HO to pathophysiology, which results from a dysregulated balance between heme and the degradation products formed by HO.

Spotlight on a New Heme Oxygenase Pathway: Testosterone-Induced Shifts in Cardiac Oxidant/Antioxidant Status.

A low testosterone level contributes to the development of oxidative damages; however, the cardiovascular effects of exogenous hormone therapy are not well elucidated. The aim of our work is to study the association of the testosterone level, antioxidant/oxidant system, and anti-inflammatory status related to the heme oxygenase (HO) system. To determine the effects of testosterone, 10-week-old, and 24-month-old sham-operated and castrated male Wistar rats were used. One part of the castrated animals was daily treated with 2.5 mg/kg cyproterone acetate, while the hormone replacement therapy was performed via an i.m. injection of a dose of 8.0 mg testosterone undecanoate/kg/once a week. The plasma testosterone level, the activity of HO and myeloperoxidase (MPO) enzymes; the concentrations of the HO-1, tumor necrosis alpha (TNF-α), and cyclic guanosine monophosphate (cGMP), as well as the total level of glutathione (GSH + GSSG) were determined from the cardiac left ventricle. In accordance with the testosterone values, the aging process and castration resulted in a decrease in antioxidant HO activity, HO-1 and cGMP concentrations and in the level of GSH + GSSG, whereas the inflammatory TNF-α and MPO activity significantly increased. Testosterone therapy was able to restore the physiological values. Our results clearly show that testosterone replacement therapy increases the antioxidant status and mitigates the inflammatory parameters via the modulation of the HO system.