Current Pharmaceutical Design - Volume 14, Issue 5, 2008

In 2003, the issue of Current Pharmaceutical Design entitled “Modulation of heme oxygenase-1 as a therapeutic target” presented six papers focused on the role and interest of heme oxygenase(HO)-1 modulation in human disease. This topic has generated significant interest in the last years leading to a growing number of publications. The purpose of this issue of Current Pharmaceutical Design is to highlight studies examining novel aspects of HO. These are important observations and point to fruitful areas for future research. All of these papers provide useful information to consider when assessing treatment strategies in human disease. By sharpening our current knowledge about the role of HO, we can better target specific interventions to a number of conditions. This issue opens with papers reporting research on HO as a therapeutic target in relevant diseases affecting metabolism, blood vessels and the central nervous system. The first article by prof. Abraham [1] describes the protective role of HO-1 in animal models of diabetes and obesity. Enhanced HO-1 expression and activity may be considered the primary defense against the deleterious effects of diabetes, metabolic syndrome and obesity. The second article by Dr. Chung [2] summarizes recent studies on HO-1 and its possible utility as a treatment for vascular diseases. Carbon monoxide is produced by HO activity and plays a protective role in vascular homeostasis, including the regulation of nitric oxide- and H2Sproducing enzymes that may be involved in either vascular protection or vascular injury. In the third article, Dr. Cuadrado [3] examines the role of HO-1 in redox homeostasis in the brain and neuroprotection. Pharmacological modulation of HO-1 has shown promising results in models of Alzheimer's, Parkinson's and of infectious diseases, such as malaria. This theme is continued by Prof. Parfenova, [4] who focuses on the functions of the constitutive isozyme, HO-2. Pharmacological inhibition or gene deletion of this enzyme in the brain exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury, whereas the end products of HO-catalyzed heme degradation have cytoprotective functions. Next, Dr. Xia and co-workers [5] review the potential of HO-1 as a modulator in T cell-mediated immune processes. As a consequence, this enzyme may provide protection in asthma, organ transplantation rejection, inflammatory bowel disease and experimental autoimmune encephalomyelitis. The last two papers that are included in this issue make a contribution to the current knowledge about pharmacological interventions in the HO pathway. With the collaboration of Dr. Motterlini [6], we have discussed our own research on inflammation, HO-1 and carbon monoxidereleasing molecules including in vitro and in vivo studies. Finally, Dr. Ferrándiz [7] has summarised a number of pharmacological approaches to induce HO-1. Perhaps one result of this issue will be to stimulate future studies that address not only basic knowledge, but also therapeutic applications. The heme oxygenase pathway provides exciting areas for future intervention-oriented research. References [1] Abraham NG, Tsenovoy PL, McClung J, Drummond GS. Heme Oxygenase: A Target Gene for Anti-Diabetic and Obesity. Curr Pharm Des 2008; 14(5): 412-421. [2] Chung H-T, Pae H-O, Cha Y-N. Role of Heme Oxygenase-1 in Vascular Disease. Curr Pharm Des 2008; 14(5): 422-428. [3] Cuadrado A, Rojo AI. Heme Oxygenase-1 As A Therapeutic Target in Neurodegenerative Diseases and Brain Infections. Curr Pharm Des 2008; 14(5): 429-442. [4] Parfenova H, Leffler CW. Cerebroprotective Functions of HO-2. Curr Pharm Des 2008; 14(5): 443-453. [5] Xia ZW, Zhong WW, Meyrowitz JS, Zhang Z. The Role of Heme Oxygenase-1 in T Cell-Mediated Immunity: The All Encompassing Enzyme. Curr Pharm Des 2008; 14(5): 454-464. [6] Alcaraz MJ, Guillen MI, Ferrandiz ML, Megías J, Motterlini R. Carbon Monoxide-Releasing Molecules: A Pharmacological Expedient to Counteract Inflammation. Curr Pharm Des 2008; 14(5): 465-472. [7] Ferrándiz ML, Devesa I. Inducers of Heme Oxygenase-1. Curr Pharm Des 2008; 14(5): 473-486.

Heme oxygenase-1 (HO-1) is central to the regulation of oxidative injury. The role of increased HO-1 expression and Heme oxygenase (HO) activity in mitigating the detrimental side effect of diabetes is examined. A review of the mechanism(s) of action is included. This may lead to the development of pharmacological and genetic approaches to mitigate the clinical complications associated with the progression of diabetes and obesity.

Great attention has been placed on the protective role of heme oxygenase-1 (HO-1) for several vascular diseases such as atherosclerosis. HO-1, by exerting anti-inflammatory, antiproliferative, anti-apoptotic and anti-oxidant effects on the vasculature, protects against atherosclerosis. The precise underlying mechanisms for HO-1-based protection are not yet completely understood, but appear to involve the protective effects of HO-1 by-products, carbon monoxide (CO), biliverdin/bilirubin and free iron. Among the HO-1 byproducts, CO has been shown to mimic some protective actions of HO-1, specifically, in vascular system. There is evidence supporting that HO-1-derived CO also interacts with other gaseous molecules, such as nitric oxide (NO) and hydrogen sulfide (H2S) that may relate to either vascular protection or injury. CO, NO and H2S not only exert comparable biological actions but also compete with and are antagonists with each other for maintaining vascular homeostasis. This review will highlight the protective roles of HO-1/CO in vascular injury/ disease, and emphasize the potential roles of CO in possible interplay among three gaseous molecules, which may be important to explore the overall protective roles of HO-1/CO system in the pathogenesis of human vascular disease.

Heme oxygenase-1 (HO-1) catalyzes the degradation of heme to generate carbon monoxide, biliverdin and free iron. Increased HO-1 levels constitute an anatomopathological feature of many neurological diseases, such as neurodegenerative disorders and brain infections, which correlate with exacerbated oxidative stress and inflammation. It is generally accepted that the elevated HO-1 levels represent an attempt to restore redox homeostasis and to down-modulate inflammation. However, experimental observations indicate that the extent of HO-1 induction may be critical because excessive heme degradation may result in toxic levels of CO, bilirubin and, more importantly, iron. Pharmacological modulation of HO-1 levels in the brain, within therapeutic limits, shows promising results in models of Alzheimer's (AD), Parkinson's (PD) and of infectious diseases, such as malaria. A more complete understanding on how HO-1 is involved in the pathogenesis of neurological diseases will be essential to develop therapeutic approaches. In the next coming years we will witness the description of chemicals, drugs or dietary products that cross the blood brain barrier efficiently, activate HO-1 expression, and achieve neuroprotective and anti-inflammatory effects in vivo.

The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via post-translational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, the end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BKCa channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of BKCa channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidant-generating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilirubin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an effective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress.

Heme oxygenase-1 (HO-1) is the rate-limiting enzyme of ferroheme metabolic pathway, which has the functions of antioxidation, anti-inflammatory, anti-apoptosis and anti-smooth muscle hyperplasia. Furthermore, HO-1 exerts a protective action in the diseases mediated by effector T lymphocytes such as T helper (Th) 1, Th2 and Th17. In addition, regulatory T cells (Treg) control the activity of CD4+CD25- effector cells in a suppressive manner. Numerous studies indicate that the protective action of HO-1 in diseases is through CD4+CD25+ Treg. This paper will review the current research and understanding of HO-1's role in T cells-mediated immunoregulation.

Carbon monoxide (CO) mediates many of the biological effects that are attributed to heme oxygenase (HO), the enzyme responsible for CO production in mammals. Antioxidant and anti-inflammatory activities of HO-1, the inducible isoform of heme oxygenase, have been demonstrated in a variety of disease models and a therapeutic exploitation of this pathway is currently under scrutiny. In this context, the liberation of CO from CO-releasing molecules (CO-RMs) is extremely attractive as these compounds may form the basis of a new class of pharmaceuticals. Recent investigations indicate that HO-1 and CO modulate important processes in chronic inflammation; these include the control of immune responses, the production of inflammatory mediators and the mitigation of cartilage or bone destruction. As HO-1 is highly expressed in the joint tissues of patients affected by arthritic diseases, it is plausible to suggest that this pathway may play a protective role against joint degenerative diseases. Studies aimed at identifying the signaling pathways responsive to endogenous CO and CO-RMs in rheumatoid arthritis and other inflammatory states are currently in progress. This research will help to elucidate the molecular mechanisms underlying the pharmacological effects of CO-RMs and may lead to the development of novel therapeutic strategies for the treatment of acute and chronic inflammatory conditions.

Heme oxygenase-1 (HO-1) is an inducible rate-limiting enzyme which catalyzes group heme into carbon monoxide, iron and bilirubin. In the recent years, HO-1 expression has been reported as an important protective endogenous mechanism against physical, chemical and biological stress. In this regard, induction of this enzyme has shown beneficial effects in several pathologic conditions, such as inflammatory processes, atherosclerosis, carcinogenesis, ischemia-reperfusion systems or degenerative diseases. Complex intracellular signalling cascades mediate the expression of HO-1 in response to external stimuli, Transcription factors, as nuclear factor E2-related factor-2, activator protein-1, and nuclear factor-kappa B, and some of their upstream kinases, mitogen-activated protein kinases, phosphatidylinositol 3-kinase, or protein kinases A, C are responsible of the HO-1 gene expression. The purpose of this article is to review the increasing number of natural and synthetic molecules reported to induce HO-1 as additive mechanism responsible for their therapeutic effects; experimental and pathological conditions as well as possible signalling mechanism involved in HO-1 expression by this compounds are described. Controlled upregulation of this enzyme, or its catalytic activity, has shown antioxidant, anti-proliferative, anti-apoptotic and anti-inflammatory properties. For this reason, pharmacologic modulation of HO- 1 system may represent an effective and cooperative strategy to intervene in several pathologic conditions.

Diabetic vascular complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Although several hyperglycemia- elicited metabolic and hemodynamic derangements have been implicated in the pathogenesis of diabetic vascular complication, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory ‘hyperglycemic memory’. Further, there is a growing body of evidence that AGEs and their receptor (RAGE) axis is involved in the pathogenesis of diabetic vascular complication. Indeed, the engagement of RAGE with AGEs is shown to elicit oxidative stress generation and subsequently evoke inflammatory responses in various types of cells, thus playing an important role in the development and progression of diabetic micro- and macroangiopathy. These observations suggest that down-regulation of RAGE expression or blockade of the RAGE downstream signaling may be a promising target for therapeutic intervention in diabetic vascular complication. In this review, we discuss several types of agents that could potentially inhibit RAGE expression or its downstream pathways and their therapeutic implications in diabetic vascular complication.

Liver ischemia-reperfusion injury occurs in a number of clinical settings, including liver surgery, transplantation, and circulatory shock, leading to significant morbidity and mortality. There is a substantial evidence that hepatic ischemia-reperfusion injury results from an intense inflammatory response initiated by oxidative stress in the liver parenchyma during reperfusion. The anti-inflammatory effects of glucocorticosteroids (GCs) have been known for decades and have found extensive therapeutic use in a wide range of clinical situations associated with organ ischemia. Based on their biological effects, routine perioperative GCs administration has been advocated to reduce hepatic ischemic injury. However, the use of GCs in hepatic surgery remains controversial and clinical benefits are still uncertain. The aim of this review is to present the experimental and clinical evidence about the role of GCs in modulating hepatic ischemiareperfusion injury.