Pathway: Cytoprotection by HMOX1
Reactions in pathway: Cytoprotection by HMOX1 :
Cytoprotection by HMOX1
Expression of heme oxygenase 1 (HMOX1) is regulated by various indicators of cell stress, while HMOX2 is expressed constitutively. Both catalyze the breakdown of heme into biliverdin (BV), carbon monoxide (CO), and ferrous iron. Biliverdin is immediately reduced to bilirubin (BIL). Both bilirubin and carbon monoxide can localize to different compartments and outside the cell. Cytoprotection by HMOX1 is exerted directly by HMOX1 and by the antioxidant metabolites produced through the degradation of heme. Additionally, due to the reactive nature of labile heme, its degradation is intrinsically protective.
HMOX1 confers cytoprotection against cell death in various models of lung and vascular injury by inhibiting apoptosis, inflammation, and immune cell proliferation. It binds to the NACHT domain of NLRP3 inflammasome, blocking its activation. In mouse it directly binds STAT3 to control the generation of pathogenic Th17 cells during neutrophilic airway inflammation. It also blocks phosphorylation of STAT3 by PTK6 and co-inhibits Socs3, a negative feedback factor of Stat3 activation, as well as RORγt, thereby decreasing Th2 and Th17 immune responses, and alleviating airway inflammation.
The beneficial effects of the three products generated by HMOX1 differ not only in their inherent molecular mechanisms, but also in their downstream cellular targets. To date, this is the only enzymatic system known to exhibit such characteristics. Iron is a vital component of many biological systems and is capable of producing hydroxyl radicals via fenton chemistry. For this reason, iron is sequestered by the storage multimer ferritin and to prevent oxidative damage while maintaining the iron pool. On the other hand, the protective effects of bilirubin and CO are broadly recognized, which has led to their consideration as therapeutics for a range of diseases. Bilirubin has been recognized as one of the most potent antioxidants in nature, and moderate increases of its serum level have been shown in numerous large-scale population and epidemiological studies to have a protective effect against cardiovascular and metabolic disease. These effects are mediated by bilirubin scavenging of superoxide anions and reactive nitrogen species (RNS), and by activating the transcription factor PPAR-alpha.
CO and biliverdin/bilirubin, have been shown to exert protective effects in the liver against a number of stimuli, as in chronic hepatitis C and in transplanted liver grafts. CO possesses intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. Binding of CO with key ferrous hemoproteins serves as a posttranslational modification that regulates important processes as diverse as aerobic metabolism, oxidative stress, and mitochondrial bioenergetics. The most important of these is the mitochondrial cytochrome c oxidase (Cco). By locally blocking mitochondrial respiration the main source of reactive oxygen species (ROS) in the cell is switched off. Additionally CO enables efficient reduction of methemoglobin (MetHb) by H2O2, thus preventing the generation of free heme in hemorrhagic diseases and malaria (Origassa and Câmara, 2013; Morse et al, 2009; Ryter et al, 2006; Cooper and Brown, 2008; Hinds and Stec, 2008).
HMOX1 confers cytoprotection against cell death in various models of lung and vascular injury by inhibiting apoptosis, inflammation, and immune cell proliferation. It binds to the NACHT domain of NLRP3 inflammasome, blocking its activation. In mouse it directly binds STAT3 to control the generation of pathogenic Th17 cells during neutrophilic airway inflammation. It also blocks phosphorylation of STAT3 by PTK6 and co-inhibits Socs3, a negative feedback factor of Stat3 activation, as well as RORγt, thereby decreasing Th2 and Th17 immune responses, and alleviating airway inflammation.
The beneficial effects of the three products generated by HMOX1 differ not only in their inherent molecular mechanisms, but also in their downstream cellular targets. To date, this is the only enzymatic system known to exhibit such characteristics. Iron is a vital component of many biological systems and is capable of producing hydroxyl radicals via fenton chemistry. For this reason, iron is sequestered by the storage multimer ferritin and to prevent oxidative damage while maintaining the iron pool. On the other hand, the protective effects of bilirubin and CO are broadly recognized, which has led to their consideration as therapeutics for a range of diseases. Bilirubin has been recognized as one of the most potent antioxidants in nature, and moderate increases of its serum level have been shown in numerous large-scale population and epidemiological studies to have a protective effect against cardiovascular and metabolic disease. These effects are mediated by bilirubin scavenging of superoxide anions and reactive nitrogen species (RNS), and by activating the transcription factor PPAR-alpha.
CO and biliverdin/bilirubin, have been shown to exert protective effects in the liver against a number of stimuli, as in chronic hepatitis C and in transplanted liver grafts. CO possesses intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. Binding of CO with key ferrous hemoproteins serves as a posttranslational modification that regulates important processes as diverse as aerobic metabolism, oxidative stress, and mitochondrial bioenergetics. The most important of these is the mitochondrial cytochrome c oxidase (Cco). By locally blocking mitochondrial respiration the main source of reactive oxygen species (ROS) in the cell is switched off. Additionally CO enables efficient reduction of methemoglobin (MetHb) by H2O2, thus preventing the generation of free heme in hemorrhagic diseases and malaria (Origassa and Câmara, 2013; Morse et al, 2009; Ryter et al, 2006; Cooper and Brown, 2008; Hinds and Stec, 2008).
Cells are subject to external molecular and physical stresses such as foreign molecules that perturb metabolic or signaling processes, and changes in temperature or pH. Cells are also subject to internal molecular stresses such as production of reactive metabolic byproducts. The ability of cells and tissues to modulate molecular processes in response to such stresses is essential to the maintenance of tissue homeostasis (Kultz 2005). Specific stress-related processes annotated here are cellular response to hypoxia, cellular response to heat stress, cellular senescence, HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand, response of EIF2AK1 (HRI) to heme deficiency, heme signaling, cellular response to chemical stress, cellular response to starvation, and unfolded protein response.
Individual cells detect and respond to diverse external molecular and physical signals. Appropriate responses to these signals are essential for normal development, maintenance of homeostasis in mature tissues, and effective defensive responses to potentially noxious agents (Kultz 2005). It is convenient, if somewhat arbitrary, to distinguish responses to signals involved in development and homeostasis from ones involved in stress responses, and that classification is followed here, with macroautophagy and responses to metal ions classified as responses to normal external stimuli, while responses to hypoxia, reactive oxygen species, and heat, and the process of cellular senescence are classified as stress responses. Signaling cascades are integral components of all of these response mechanisms but because of their number and diversity, they are grouped in a separate signal transduction superpathway in Reactome.