Association of Heme Oxygenase 1 with the Restoration of Liver Function after Damage in Murine Malaria by Plasmodium yoelii

The liver efficiently restores function after damage induced during malarial infection once the parasites are cleared from the blood. However, the molecular events leading to the restoration of liver function after malaria are still obscure. To study this, we developed a suitable model wherein mice infected with Plasmodium yoelii (45% parasitemia) were treated with the antimalarial α/β-arteether to clear parasites from the blood and, subsequently, restoration of liver function was monitored. Liver function tests clearly indicated that complete recovery of liver function occurred after 25 days of parasite clearance. Analyses of proinflammatory gene expression and neutrophil infiltration further indicated that hepatic inflammation, which was induced immediately after parasite clearance from the blood, was gradually reduced. Moreover, the inflammation in the liver after parasite clearance was found to be correlated positively with oxidative stress and hepatocyte apoptosis. We investigated the role of heme oxygenase 1 (HO-1) in the restoration of liver function after malaria because HO-1 normally renders protection against inflammation, oxidative stress, and apoptosis under various pathological conditions. The expression and activity of HO-1 were found to be increased significantly after parasite clearance. We even found that chemical silencing of HO-1 by use of zinc protoporphyrin enhanced inflammation, oxidative stress, hepatocyte apoptosis, and liver injury. In contrast, stimulation of HO-1 by cobalt protoporphyrin alleviated liver inflammation and reduced oxidative stress, hepatocyte apoptosis, and associated tissue injury. Therefore, we propose that selective induction of HO-1 in the liver would be beneficial for the restoration of liver function after parasite clearance.     

Targeting endothelial cells with heme oxygenase-1 gene using VE-cadherin promoter attenuates hyperglycemia-mediated cell injury and apoptosis

Risk factors for cardiovascular diseases include hyperglycemia, TNF, and reactive oxygen species (ROS), which collectively contribute to vascular endothelial cell dysfunction and apoptosis. We examined, in vascular endothelial cells, whether the selective expression of heme oxygenase-1 (HO-1) offers cytoprotection against glucose- and TNF-mediated cell death. An adenoviral vector expressing human HO-1 was constructed using a VE-cadherin (VECAD) promotor fragment, and cell-specific expression of the recombinant adenovirus was examined using endothelial and vascular smooth muscle cells. The effects of HO-1 transduction (Ad-VECAD-HO-1 gene) on HO-1 expression, HO activity, and the response to TNF and hyperglycemia were studied. Human HO-1 gene was selectively expressed in endothelial cells after infection with the Ad-VECAD-HO-1 vector. Selective expression of HO-1 prevented TNF- and hyperglycemia-mediated superoxide (O2-) formation, DNA degeneration, and upregulation of caspase, but increased the expression of pAkt and Bcl-xL, proteins responsible for endothelial dysfunction in diabetes. These results demonstrate that endothelial cell survival after oxidative stress injury may be enhanced by targeting HO-1 expression, thus blocking inflammation, apoptosis, and thereby attenuating cardiovascular risk factors.     

Exacerbation of oxidative stress-induced cell death and differentiation in induced pluripotent stem cells lacking heme oxygenase-1

Embryonic stem cells (ESCs) are promising donor sources in cell therapies for various diseases. Although low levels of reactive oxygen species (ROS) are necessary for the maintenance of stem cells, increased ROS levels initiate differentiation and cell damage. We and others have previously demonstrated that heme oxygenase (HO)-1, a stress response protein with antioxidative and anti-inflammatory properties, plays critical protective functions in cardiovascular and other diseases. However, the functions of HO-1 in ESCs remain to be elucidated. Our goal was to investigate the roles of HO-1 in ESC survival and differentiation. Due to the lack of HO-1-deficient ESCs, we used Oct3/4, Sox2, c-Myc, and Klf4 retroviruses to reprogram mouse embryonic fibroblasts into induced pluripotent stem (iPS) cells of different HO-1 genotypes. These iPS-HO-1 cells exhibited characteristics of mouse ESCs (mESCs) and formed teratomas that were composed of cell types of all 3 germ layers after injected into severe combined immunodeficiency mice. In response to oxidant stress, iPS-HO-1(-/-) cells accumulated higher levels of intracellular ROS compared with D3 mESCs or iPS-HO-1(+/+) cells and were more prone to oxidant-induced cell death. Spontaneous differentiation experiments revealed that Oct4 levels were significantly lower in iPS-HO-1(-/-) cells after leukemia inhibitory factor withdrawal and removal of feeders. Further, during the course of spontaneous differentiation, iPS-HO-1(-/-) cells had enhanced Erk1/2 phosphorylation, which has been linked to ESC differentiation. By the loss-of-function approach using iPS-HO-1(-/-) cells, our results demonstrate that a lack of HO-1 renders iPS cells more prone to oxidative stress-induced cell death and differentiation.     

Cytochrome P450 gender-related differences in response to hyperoxia in young CBA mice

Cytochrome P450 monooxygenases (CYPs) represent large class of heme-containing enzymes that catalyze the metabolism of various endogenous and exogenous substrates. Although they are found in many tissues, the function of the particular subset of their isoforms does not appear to be the same. Many CYP genes exhibit sexually dimorphic expression, while others are sex-independent. Moreover, as a source of reactive oxygen species (ROS), P450 system is believed to play the important role in various pathological conditions and diseases. The aim of this study was to observe the effect of hyperoxia on oxidant/antioxidant status in the liver of young male and female mice and to determine whether the observed effects are associated with the expression of Heme oxygenase-1 (HO-1) and CYP genes associated with stress (Cyp1a1, Cyp1a2, Cyp2a5, and Cyp2e1) or stress and gender-related responses (Cyp2b9). In this study, we demonstrated gender-related effect of hyperoxia on oxidant/antioxidant status and on expression of certain P450 enzymes. Our results suggest that females are less susceptible to hyperoxia induced oxidative stress by two major mechanisms: upregulated expression of HO-1 genes and different expression of certain P450 enzymes. Therefore, our study could provide additional data of gender-dependent responses in susceptibility to oxidative stress, chemical toxicity and drug efficiency in treatment of diseases.     

一氧化氮和内质网应激

一氧化氮(nitric oxide,NO)是一种重要的多功能内源性气体分子,能舒张血管、参与免疫反应和作为一种神经递质在神经元的信息传递中发挥重要作用,因而广泛参与机体心血管系统、神经系统和免疫系统等的生理和病理调节[1].     

Heme oxygenase-1 in tumors: is it a false friend?

Heme oxygenase-1 (HO-1) catalyzes the oxidation of heme to biologically active products: carbon monoxide (CO), biliverdin, and ferrous iron. It participates in maintaining cellular homeostasis and plays an important protective role in the tissues by reducing oxidative injury, attenuating the inflammatory response, inhibiting cell apoptosis, and regulating cell proliferation. HO-1 is also an important proangiogenic mediator. Most studies have focused on the role of HO-1 in cardiovascular diseases, in which its significant, beneficial activity is well recognized. A growing body of evidence indicates, however, that HO-1 activation may play a role in carcinogenesis and can potently influence the growth and metastasis of tumors. HO-1 is very often upregulated in tumor tissues, and its expression is further increased in response to therapies. Although the exact effect can be tissue specific, HO-1 can be regarded as an enzyme facilitating tumor progression. Accordingly, inhibition of HO-1 can be suggested as a potential therapeutic approach sensitizing tumors to radiation, chemotherapy, or photodynamic therapy.     

The effects of acetylcholinesterase inhibitors on the heart in acute myocardial infarction and heart failure: From cells to patient reports

Cardiovascular diseases remain a major cause of morbidity and mortality worldwide. Cardiovascular diseases such as acute myocardial infarction, ischaemia/reperfusion injury and heart failure are associated with cardiac autonomic imbalance characterized by sympathetic overactivity and parasympathetic withdrawal from the heart. Increased parasympathetic activity by electrical vagal nerve stimulation has been shown to provide beneficial effects in the case of cardiovascular diseases in both animals and patients by improving autonomic function, cardiac remodelling and mitochondrial function. However, clinical limitations for electrical vagal nerve stimulation exist because of its invasive nature, costly equipment and limited clinical validation. Therefore, novel therapeutic approaches which moderate parasympathetic activities could be beneficial for in the case of cardiovascular disease. Acetylcholinesterase inhibitors inhibit acetylcholinesterase and hence increase cholinergic transmission. Recent studies have reported that acetylcholinesterase inhibitors improve autonomic function and cardiac function in cardiovascular disease models. Despite its potential clinical benefits for cardiovascular disease patients, the role of acetylcholinesterase inhibitors in acute myocardial infarction and heart failure remediation remains unclear. This article comprehensively reviews the effects of acetylcholinesterase inhibitors on the heart in acute myocardial infarction and heart failure scenarios from in vitro and in vivo studies to clinical reports. The mechanisms involved are also discussed in this review.     

Mechanisms of Apoptosis in the Heart

Apoptosis is a complex and highly regulated form of cell death, and believed to contribute to the continuous decline of ventricular function in heart failure. Apoptotic cell death is observed in a variety of cardiovascular diseases, including myocardial infarction, ischemia-reperfusion injury, end-stage heart failure, arrhythmias, and adriamycin cardiomyopathy. There are several pathways leading to programmed cell death. Apoptosis can be initiated by extracellular or intracellular stimuli, leading to the activation of caspases and subsequent cell death. A better understanding of the process of apoptosis in the heart is clearly important as it may lead to the identification of novel therapies for cardiovascular disease. This review is focused on the basic cellular mechanisms of apoptosis, as well as our current understanding of this process in the heart.     

Induction of heme oxygenase-1 expression inhibits platelet-dependent thrombosis

Heme oxygenase-1 (HO-1) plays a key role in protecting tissue from oxidative stress. Although some studies implicate HO-1 in modulating thrombosis after vascular injury, the impact of HO-1 on the rate of clot formation in vivo is poorly defined. This study examined the potential function of HO-1 in regulating platelet-dependent arterial thrombosis. Platelet-rich thrombi were induced in C57BL/6J mice by applying 10% ferric chloride to the exposed carotid artery. Mean occlusion time of wild-type mice (n = 10) was 14.6 +/- 1.0 min versus 12.9 +/- 0.6 min for HO-1-/- mice (n = 11, p = 0.17). However, after challenge with hemin, mean occlusion time was significantly longer in wild-type mice (16.3 +/- 1.2 min, n = 15) than HO-1-/- mice (12.0 +/- 1.0 min, n = 9; p = 0.021). Hemin administration induced an approximately twofold increase in oxidative stress, measured as plasma thiobarbituric acid reactive substances. Immunohistochemical analysis revealed that hemin induced a robust increase in HO-1 expression within the carotid arterial wall. Ex vivo blood clotting within a collagen-coated perfusion chamber was studied to determine whether the accelerated thrombosis observed in HO-1-/- mice was contributed to by effects on the blood itself. Under basal conditions, mean clot formation during perfusion of blood over collagen did not differ between wild-type mice and HO-1-/- mice. However, after hemin challenge, mean clot formation was significantly increased in HO-1-/- mice compared with wild-type controls. These results suggest that, under basal conditions, HO-1 does not exert a significant effect on platelet-dependent clot formation in vivo. However, under conditions that stimulate HO-1 production, platelet-dependent thrombus formation is inhibited by HO-1. Enhanced HO-1 expression in response to oxidative stress may represent an adaptive response mechanism to down-regulate platelet activation under prothrombotic conditions.     

The role of carbon monoxide in the gastrointestinal tract

Carbon monoxide (CO) is a biologically active product of haem metabolism that contributes to the normal physiology of the gastrointestinal tract. In this article, we review recent data showing that CO is an integral regulator of gastrointestinal motility and an important factor in the response to gastrointestinal injury. CO is generated by haem oxygenase-2 (HO-2), which is constitutively expressed in many inhibitory neurones of the vertebrate enteric nervous system. The membrane potential gradients along and across the muscle layers of the gastrointestinal tract require the generation of CO by haem oxygenase-2. The presence of CO is also necessary for normal inhibitory neurotransmission in circular smooth muscle and appears to permit nitric oxide-mediated inhibitory neurotransmission. Genetic deletion of the haem oxygenase-2 gene in mice slows gut transit. The other major CO synthetic enzyme, haem oxygenase-1 (HO-1) is induced under conditions of stress or injury. Recent studies have demonstrated that up-regulation of haem oxygenase-1 protects the gut from several types of gastrointestinal injury, suggesting that CO or induction of HO-1 may find therapeutic use in gastrointestinal diseases and injuries. Furthermore, it is anticipated that the understanding of CO-mediated signalling in the gastrointestinal tract will inform studies in other tissues that express haem oxygenases.     

Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease

Throughout the last 2 decades, experimental evidence from in vitro studies and preclinical models of disease has demonstrated that reactive oxygen and nitrogen species, including the reactive oxidant peroxynitrite, are generated in parenchymal, endothelial, and infiltrating inflammatory cells during stroke, myocardial and other forms of reperfusion injury, myocardial hypertrophy and heart failure, cardiomyopathies, circulatory shock, cardiovascular aging, atherosclerosis and vascular remodeling after injury, diabetic complications, and neurodegenerative disorders. Peroxynitrite and other reactive species induce oxidative DNA damage and consequent activation of the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1), the most abundant isoform of the PARP enzyme family. PARP overactivation depletes its substrate NAD(+), slowing the rate of glycolysis, electron transport, and ATP formation, eventually leading to functional impairment or death of cells, as well as up-regulation of various proinflammatory pathways. In related animal models of disease, peroxynitrite neutralization or pharmacological inhibition of PARP provides significant therapeutic benefits. Therefore, novel antioxidants and PARP inhibitors have entered clinical development for the experimental therapy of various cardiovascular and other diseases. This review focuses on the human data available on the pathophysiological relevance of the peroxynitrite-PARP pathway in a wide range of disparate diseases, ranging from myocardial ischemia/reperfusion injury, myocarditis, heart failure, circulatory shock, and diabetic complications to atherosclerosis, arthritis, colitis, and neurodegenerative disorders.     

Heme oxygenase-1 and the vascular bed: from molecular mechanisms to therapeutic opportunities

Heme oxygenase-1, an enzyme degrading heme to carbon monoxide, iron, and biliverdin, has been recognized as playing a crucial role in cellular defense against stressful conditions, not only related to heme release. HO-1 protects endothelial cells from apoptosis, is involved in blood-vessel relaxation regulating vascular tone, attenuates inflammatory response in the vessel wall, and participates in blood-vessel formation by means of angiogenesis and vasculogenesis. The latter functions link HO-1 not only to cardiovascular ischemia but also to many other conditions that, like development, wound healing, or cancer, are dependent on neovascularization. The aim of this comprehensive review is to address the mechanisms of HO-1 regulation and function in cardiovascular physiology and pathology and to demonstrate some possible applications of the vast knowledge generated so far. Recent data provide powerful evidence for the involvement of HO-1 in the therapeutic effect of drugs used in cardiovascular diseases. Novel studies open the possibilities of application of HO-1 for gene and cell therapy. Therefore, research in forthcoming years should help to elucidate both the real role of HO-1 in the effect of drugs and the clinical feasibility of HO-1-based cell and gene therapy, creating the effective therapeutic avenues for this refined antioxidant system.     

免疫细胞在心肌重塑中的作用

心肌重塑几乎与所有类型的心脏疾病的发生发展相关,是一个重要的全球性健康问题.这种病理性重塑过程包括心室扩张、心肌炎症反应和心肌细胞肥大,最终导致心力衰竭的发生.在各种类型的心肌损伤后,心脏从纤维细胞转化为肌成纤维细胞,随后并沉积在细胞外基质中,这是心肌纤维化的重要病理机制.同时免疫细胞的激活及其介导的炎症反应也参与了心肌重塑的发生与发展,因而了解免疫细胞导致心肌重塑的可能病理机制可为临床防治和逆转心肌重塑提供新的靶点.     

The immunoproteasome controls the availability of the cardioprotective pattern recognition molecule Pentraxin3

Cardiomyocyte death as a result of viral infection is an excellent model for dissecting the inflammatory stress response that occurs in heart tissue. We reported earlier that a specific proteasome isoform, the immunoproteasome, prevents exacerbation of coxsackievirus B3 (CVB3)‐induced myocardial destruction and preserves cell vitality in heart tissue inflammation. Following the aim to decipher molecular targets of immunoproteasome‐dependent proteolysis, we investigated the function and regulation of the soluble PRR Pentraxin3 (PTX3). We show that the ablation of PTX3 in mice aggravated CVB3‐triggered inflammatory injury of heart tissue, without having any significant effect on viral titers. Thus, there might be a role of PTX3 in preventing damage‐associated molecular pattern‐induced cell death. We found that the catalytic activity of the immunoproteasome subunit LMP7 regulates the timely availability of factors controlling PTX3 production. We report on immunoproteasome‐dependent alteration of ERK1/2 and p38MAPKs, which were both found to be involved in PTX3 expression control. Our finding of a cardioprotective function of immunoproteasome‐dependent PTX3 expression revealed a crucial mechanism of the stress‐induced damage response in myocardial inflammation. In addition to antigen presentation and cytokine production, proteolysis by the immunoproteasome can also regulate the innate immune response during viral infection.     

Redox regulation of heat shock protein expression by signaling involving nitric oxide and carbon monoxide: relevance to brain aging, neurodegenerative disorders, and longevity

Increased free radical generation and decreased efficiency of the reparative/degradative mechanisms both primarily contribute to age-related elevation in the level of oxidative stress and brain damage. Excess formation of reactive oxygen and nitrogen species can cause proteasomal dysfunction and protein overloading. The major neurodegenerative diseases are all associated with the presence of abnormal proteins. Different integrated responses exist in the brain to detect oxidative stress which is controlled by several genes termed vitagenes, including the heat shock protein (HSP) system. Of the various HSPs, heme oxygenase-I (HO-1), by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. The HO-1 gene is redox regulated and its expression is modulated by redox active compounds, including nutritional antioxidants. Given the broad cytoprotective properties of the heat shock response, there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. These findings have opened up new neuroprotective strategies, as molecules inducing this defense mechanism can be a therapeutic target to minimize the deleterious consequences associated with accumulation of conformationally aberrant proteins to oxidative stress, such as in neurodegenerative disorders and brain aging, with resulting prolongation of a healthy life span.     

Deletion of caveolin-1 protects against oxidative lung injury via up-regulation of heme oxygenase-1

Acute lung injury (ALI) is a major cause of morbidity and mortality in critically ill patients. Hyperoxia causes lung injury in animals and humans, and is an established model of ALI. Caveolin-1, a major constituent of caveolae, regulates numerous biological processes, including cell death and proliferation. Here we demonstrate that caveolin-1-null mice (cav-1(-/-)) were resistant to hyperoxia-induced death and lung injury. Cav-1(-/-) mice sustained reduced lung injury after hyperoxia as determined by protein levels in bronchoalveolar lavage fluid and histologic analysis. Furthermore, cav-1(-/-) fibroblasts and endothelial cells and cav-1 knockdown epithelial cells resisted hyperoxia-induced cell death in vitro. Basal and inducible expression of the stress protein heme oxygenase-1 (HO-1) were markedly elevated in lung tissue or fibroblasts from cav-1(-/-) mice. Hyperoxia induced the physical interaction between cav-1 and HO-1 in fibroblasts assessed by co-immunoprecipitation studies, which resulted in attenuation of HO activity. Inhibition of HO activity with tin protoporphyrin-IX abolished the survival benefits of cav-1(-/-) cells and cav-1(-/-) mice exposed to hyperoxia. The cav-1(-/-) mice displayed elevated phospho-p38 mitogen-activated protein kinase (MAPK) and p38beta expression in lung tissue/cells under basal conditions and during hyperoxia. Treatment with SB202190, an inhibitor of p38 MAPK, decreased hyperoxia-inducible HO-1 expression in wild-type and cav-1(-/-) fibroblasts. Taken together, our data demonstrated that cav-1 deletion protects against hyperoxia-induced lung injury, involving in part the modulation of the HO-1-cav-1 interaction, and the enhanced induction of HO-1 through a p38 MAPK-mediated pathway. These studies identify caveolin-1 as a novel component involved in hyperoxia-induced lung injury.     

Hemodynamic responses during psychological stress: Implications for studying disease processes

Investigation of the physiological correlates of psychological stress is of interest in relation to the putative impact of stress in the etiology of cardiovascular disease. Although the assessment of blood pressure and heart rate responses to psychological stress has been very informative, the addition of cardiac output measurement has added a further dimension to this research field. In recent studies, a more complete hemodynamic picture of the stress response has been documented in terms of cardiac output and systemic vascular resistance components of blood pressure changes. Different stressors have been shown to produce similar blood pressure increases due to quite different hemodynamic mechanisms. Furthermore, when faced with the same stressor, different individuals may exhibit pressor responses that are very different hemodynamically. There is growing evidence that these hemodynamic response patterns to psychological stress are stable individual traits. Response stability is a prerequisite for considering how stress-related hemodynamic changes may be implicated in the pathophysiology of cardiovascular diseases. Observations that hemodynamic response patterns in individuals at higher risk for the development of hypertension differ from those of lower risk individuals show that specific patterns of hemodynamic response are associated with disease processes. Although it is as yet unclear whether they represent markers or mechanisms. Overall. hemodynamic studies appear to he helping to refine our understanding of how stress can impact cardiovascular disease processes.     

A review on heme oxygenase-1 induction: is it a necessary evil

Heme oxygenase-1 (HO-1) is considered to be the main protein in diseases arising as a result of oxidative and inflammatory insults. Tremendous research has been carried out on HO-1 since years, pertaining its cytoprotective effect against oxidative injury and other cellular stresses. HO-1, by regulating intracellular levels of pro-oxidant heme, or by other benefits of its by-products such as carbon monoxide (CO) and biliverdin (BV) had become an important candidate protein to be up-regulated to combat diverse stressful events. Although the beneficial effects of HO-1 induction have been reported in a number of cells and tissues, a growing body of evidence indicates that this increased HO-1 expression may lead to the progression of several diseases such as neurodegeneration, carcinogenesis. But it is not clear, what accounts for the increased expression of HO-1 in cells and tissues. The observed friendly role of HO-1 in a wide range of stress conditions since times is now doubtful. Therefore, more studies are needed to elucidate the exact role of HO-1 in various stressful events. Being more concise, elucidating the effect of HO-1 up-regulation on critical genes involved in particular diseases such as cancer will help to a larger extent to comprehend the exact role of HO-1. This review will assist in understanding the dual role (protective and detrimental) of HO-1 and the signaling pathway involved and will help in unraveling the doubtful role of HO-1 induction.     

What is a role of haeme oxygenase‐1 in psoriasis? Current concepts of pathogenesis

The skin is constantly exposed to endogenous and environmental pro-oxidant agents, which lead to harmful generation of reactive oxygen species (ROS). Healthy skin, being a potential target for oxidative stress, is equipped with a large number of defence mechanisms including antioxidant systems. This protection can be corrupted by an imbalance between ROS and antioxidants with pathological level of oxidants prevailing. There is a great body of evidence indicating that some inflammatory skin diseases, such as psoriasis, are mediated by oxidative stress. Keratinocytes of normal skin, the primary target for pro-oxidant agents, show strong expression of ROS-detoxifying enzymes. In addition, normal keratinocytes express haeme oxygenase (HO), an enzyme which might be involved in the protection of cells against oxidative stress. HO (inducible HO-1, constitutive HO-2 and HO-3) is the rate-limiting enzyme in haeme catabolism, which leads to the generation of biliverdin, iron, and carbon monoxide. HO-1 is a stress-responsive protein whose expression is induced by various oxidative agents. HO-1 is known for its cytoprotective, antioxidant and anti-inflammatory properties. Interestingly, a strong overexpression of HO-1 was observed in psoriatic skin. However, the role of HO-1 in psoriasis remains unclear. In this review, we will discuss some current concepts concerning pathogenesis of psoriasis and the contribution of HO-1 in skin inflammation to show the relationships between HO-1, ROS and cytokine network in psoriatic skin. We will try to answer a question whether enhanced HO-1 expression in keratinocytes results in beneficial or detrimental effect on the development and severity of psoriatic lesions.     

Therapeutic applications of bilirubin and biliverdin in transplantation

Bilirubin is the end product of heme catabolism by heme oxygenases. The inducible form of these enzymes is heme oxygenase-1 (HO-1), which is the rate-limiting enzyme that can degrade heme into equimolar quantities of carbon monoxide (CO), biliverdin, and free iron. Biliverdin is very rapidly converted to bilirubin by the enzyme biliverdin reductase, and free iron upregulates the expression of ferritin. HO-1 is a ubiquitous stress protein and is induced in many cell types by various stimuli. Induced HO-1 exerts antiinflammatory effects and modulates apoptosis. Expression of HO-1 in vivo suppresses the inflammatory responses in endotoxic shock, hyperoxia, acute pleurisy, and organ transplantation, as well as ischemia-reperfusion injury, and thereby provides salutary effects in these conditions. Accumulating evidence indicates that biliverdin/bilirubin can mediate the protective effects of HO-1 in many disease models, such as IRI and organ transplantation, via its antiinflammatory, antiapoptotic, antiproliferative, and antioxidant properties, as well as its effects on the immune response. This review attempts to summarize these protective roles as well as the molecular mechanisms by which biliverdin/bilirubin benefit IRI and solid-organ transplantation, including chronic rejection, and islet transplantation.