Where is the Clinical Breakthrough of Heme Oxygenase-1 / Carbon Monoxide Therapeutics?

2018 ◽  
Vol 24 (20) ◽  
pp. 2264-2282 ◽  
Author(s):  
Christopher P. Hopper ◽  
Lorenz Meinel ◽  
Christoph Steiger ◽  
Leo E. Otterbein
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Capital Investment ◽  
Therapeutic Potential ◽  
Heme Oxygenase 1 ◽  
Commercial Development ◽  
Protective Enzyme ◽  
Rate Limiting Step ◽  
Rate Limiting ◽  
Development Perspective

Heme oxygenase (HO), the rate-limiting step in the degradation of heme to biliverdin, ferrous ion, and carbon monoxide (CO), is an ancestral protective enzyme conserved across phylogenetic domains. While HO was first described in the late 1960s and progressively characterized in the following decades, there has been a surge of innovation over the past twenty years in efforts to leverage the cytoprotective power of HO in a clinical setting. Despite the plethora of preclinical data indicating extraordinary therapeutic potential, HO has remained elusive from the physician’s toolbox. The leading candidate in development, CO, has long been misconstrued as a useless toxic gas. Scientists have crafted an array of CO delivery molecules and devices to harness HO, however, each endeavor was met with limitations preventing translation into clinical practice. In this discussion, we summarize the HO / CO field with a clinical and commercial development perspective. More specifically, given the enormous global efforts and capital investment into the field, we ask: where is the breakthrough therapy?

An internal enhancer regulates heme- and cadmium-mediated induction of human heme oxygenase-1

2003 ◽  
Vol 285 (3) ◽  
pp. F515-F523 ◽  
Author(s):  
Nathalie Hill-Kapturczak ◽  
Eric Sikorski ◽  
Christy Voakes ◽  
Jairo Garcia ◽  
Harry S. Nick ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Tissue Injury ◽  
Molecular Regulation ◽  
Heme Oxygenase 1 ◽  
Aortic Endothelial Cells ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Beneficial Response ◽  
Enhancer Function ◽  
Rate Limiting

Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme degradation, releasing iron, carbon monoxide, and biliverdin. Induction of HO-1 is an adaptive and beneficial response in renal and nonrenal settings of tissue injury. The purpose of this study was to characterize the regulation of the human HO-1 gene in renal proximal tubule and aortic endothelial cells in response to heme and cadmium. Evaluation of multiple human HO-1 promoter-reporter constructs up to -9.1 kb demonstrated only a partial response to heme and cadmium. In an effort to mimic endogenous stimulus-dependent levels of HO-1 induction, we evaluated the entire 12.5 kb of the human HO-1 gene, including introns and exons, in conjunction with a -4.5-kb human HO-1 promoter and observed significant heme- and cadmium-mediated induction of the reporter gene, suggesting the presence of an internal enhancer. Enhancer function was orientation independent and required a region between -3.5 and -4.5 kb of the human HO-1 promoter. Our studies identified a novel enhancer internal to the human HO-1 gene that, in conjunction with the HO-1 promoter, recapitulates heme- and cadmium-mediated induction of the endogenous HO-1 gene. Elucidation of the molecular regulation of the human HO-1 gene will allow for the development of therapeutic strategies to manipulate HO-1 gene expression in pathological states.

scholarly journals Therapeutic Potential of Heme Oxygenase-1/Carbon Monoxide in Lung Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
Myrna Constantin ◽  
Alexander J. S. Choi ◽  
Suzanne M. Cloonan ◽  
Stefan W. Ryter
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Heme Oxygenase 1 ◽  
Protective Mechanism ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Oxidative Breakdown ◽  
Biliverdin Ix

Heme oxygenase (HO), a catabolic enzyme, provides the rate-limiting step in the oxidative breakdown of heme, to generate carbon monoxide (CO), iron, and biliverdin-IXα. Induction of the inducible form, HO-1, in tissues is generally regarded as a protective mechanism. Over the last decade, considerable progress has been made in defining the therapeutic potential of HO-1 in a number of preclinical models of lung tissue injury and disease. Likewise, tissue-protective effects of CO, when applied at low concentration, have been observed in many of these models. Recent studies have expanded this concept to include chemical CO-releasing molecules (CORMs). Collectively, salutary effects of the HO-1/CO system have been demonstrated in lung inflammation/acute lung injury, lung and vascular transplantation, sepsis, and pulmonary hypertension models. The beneficial effects of HO-1/CO are conveyed in part through the inhibition or modulation of inflammatory, apoptotic, and proliferative processes. Recent advances, however, suggest that the regulation of autophagy and the preservation of mitochondrial homeostasis may serve as additional candidate mechanisms. Further preclinical and clinical trials are needed to ascertain the therapeutic potential of HO-1/CO in human clinical disease.

Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications

2006 ◽  
Vol 86 (2) ◽  
pp. 583-650 ◽  
Author(s):  
Stefan W. Ryter ◽  
Jawed Alam ◽  
Augustine M. K. Choi
Keyword(s):  
Carbon Monoxide ◽  
Cellular Proliferation ◽  
Biochemical Characterization ◽  
Apoptotic Cell ◽  
Heme Oxygenase 1 ◽  
Bile Pigments ◽  
Cellular Functions ◽  
Rate Limiting Step ◽  
Rate Limiting

The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO). In recent years, endogenously produced CO has been shown to possess intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. The era of gaseous molecules in biomedical research and human diseases initiated with the discovery that the endothelial cell-derived relaxing factor was identical to the gaseous molecule nitric oxide (NO). The discovery that endogenously produced gaseous molecules such as NO and now CO can impart potent physiological and biological effector functions truly represented a paradigm shift and unraveled new avenues of intense investigations. This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress. Furthermore, the current understanding of the functional significance of HO shall be discussed from the perspective of each of the metabolic by-products, with a special emphasis on CO. Finally, this presentation aspires to lay a foundation for potential future clinical applications of these systems.

scholarly journals Heme Oxygenase-1 Signaling and Redox Homeostasis in Physiopathological Conditions

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 589
Author(s):  
Valeria Consoli ◽  
Valeria Sorrenti ◽  
Salvo Grosso ◽  
Luca Vanella
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Redox Homeostasis ◽  
Transformation Products ◽  
Antioxidant Response ◽  
Heme Oxygenase 1 ◽  
Ferrous Ions ◽  
Biliverdin Reductase ◽  
Rate Limiting Step

Heme-oxygenase is the enzyme responsible for degradation of endogenous iron protoporphyirin heme; it catalyzes the reaction’s rate-limiting step, resulting in the release of carbon monoxide (CO), ferrous ions, and biliverdin (BV), which is successively reduced in bilirubin (BR) by biliverdin reductase. Several studies have drawn attention to the controversial role of HO-1, the enzyme inducible isoform, pointing out its implications in cancer and other diseases development, but also underlining the importance of its antioxidant activity. The contribution of HO-1 in redox homeostasis leads to a relevant decrease in cells oxidative damage, which can be reconducted to its cytoprotective effects explicated alongside other endogenous mechanisms involving genes like TIGAR (TP53-induced glycolysis and apoptosis regulator), but also to the therapeutic functions of heme main transformation products, especially carbon monoxide (CO), which has been shown to be effective on GSH levels implementation sustaining body’s antioxidant response to oxidative stress. The aim of this review was to collect most of the knowledge on HO-1 from literature, analyzing different perspectives to try and put forward a hypothesis on revealing yet unknown HO-1-involved pathways that could be useful to promote development of new therapeutical strategies, and lay the foundation for further investigation to fully understand this important antioxidant system.

scholarly journals 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

2020 ◽  
Vol 22 (1) ◽  
pp. 47
Author(s):  
Tamás Gáll ◽  
Dávid Pethő ◽  
Annamária Nagy ◽  
György Balla ◽  
József Balla
Keyword(s):  
Carbon Monoxide ◽  
Hydrogen Sulfide ◽  
Heme Oxygenase ◽  
Therapeutic Potential ◽  
Cellular Metabolism ◽  
Heme Oxygenase 1 ◽  
New Therapeutic Approaches ◽  
Hemoglobin Oxidation ◽  
Biological Responses ◽  
Human Disorders

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.

Involvement of Heme Oxygenase-1 in Neuropsychiatric and Neurodegenerative Diseases

2018 ◽  
Vol 24 (20) ◽  
pp. 2283-2302 ◽  
Author(s):  
Vivian B. Neis ◽  
Priscila B. Rosa ◽  
Morgana Moretti ◽  
Ana Lucia S. Rodrigues
Keyword(s):  
Neurodegenerative Diseases ◽  
Heme Oxygenase ◽  
Therapeutic Potential ◽  
Redox Homeostasis ◽  
Antioxidant Defenses ◽  
Heme Oxygenase 1 ◽  
Physiological Conditions ◽  
And Oxidative Stress ◽  
Defensive Mechanism

Heme oxygenase (HO) family catalyzes the conversion of heme into free iron, carbon monoxide and biliverdin. It possesses two well-characterized isoforms: HO-1 and HO-2. Under brain physiological conditions, the expression of HO-2 is constitutive, abundant and ubiquitous, whereas HO-1 mRNA and protein are restricted to small populations of neurons and neuroglia. HO-1 is an inducible enzyme that has been shown to participate as an essential defensive mechanism for neurons exposed to oxidant challenges, being related to antioxidant defenses in certain neuropathological conditions. Considering that neurodegenerative diseases (Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Multiple Sclerosis (MS)) and neuropsychiatric disorders (depression, anxiety, Bipolar Disorder (BD) and schizophrenia) are associated with increased inflammatory markers, impaired redox homeostasis and oxidative stress, conditions that may be associated with alterations in HO-levels/activity, the purpose of this review is to present evidence on the possible role of HO-1 in these Central Nervous System (CNS) diseases. In addition, the possible therapeutic potential of targeting brain HO-1 is explored in this review.

scholarly journals Heme oxygenase-1 and carbon monoxide in pulmonary medicine

2003 ◽  
Vol 4 (1) ◽  
Author(s):  
Dirk-Jan Slebos ◽  
Stefan W Ryter ◽  
Augustine MK Choi
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Pulmonary Medicine
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