scholarly journals Endogenous Carbon Monoxide Signaling Modulates Mitochondrial Function and Intracellular Glucose Utilization: Impact of the Heme Oxygenase Substrate Hemin

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 652 ◽  
Author(s):  
David Stucki ◽  
Julia Steinhausen ◽  
Philipp Westhoff ◽  
Heide Krahl ◽  
Dominik Brilhaus ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Glucose Metabolism ◽  
Respiratory Chain ◽  
Heme Oxygenase ◽  
Antioxidant Defense ◽  
Redox Cycling ◽  
Short Term ◽  
Heme Oxygenases ◽  
Cycling System

Stress-inducible heme oxygenase-1 (HO-1) catalyzes the oxidative cleavage of heme yielding biliverdin, ferrous iron, and carbon monoxide (CO). Heme oxygenase activity has been attributed to antioxidant defense via the redox cycling system of biliverdin and bilirubin. There is increasing evidence that CO is a gaseous signaling molecule and plays a role in the regulation of energy metabolism. Inhibitory effects of CO on the respiratory chain are well established, but the implication of such a process on the cellular stress response is not well understood. By means of extracellular flux analyses and isotopic tracing, we studied the effects of CO, either released from the CO donor CORM-401 or endogenously produced by heme oxygenases, on the respiratory chain and glucose metabolism. CORM-401 was thereby used as a tool to mimic endogenous CO production by heme oxygenases. In the long term (>60 min), CORM-401-derived CO exposure inhibited mitochondrial respiration, which was compensated by increased glycolysis accompanied by a loss of the ATP production rate and an increase in proton leakage. This effect pattern was likewise observed after endogenous CO production by heme oxygenases. However, in the present setting, these effects were only observed when sufficient substrate for heme oxygenases (hemin) was provided. Modulation of the HO-1 protein level was less important. The long-term influence of CO on glucose metabolism via glycolysis was preceded by a short-term response (<30 min) of the cells to CO. Stable isotope-labeling experiments and metabolic flux analysis revealed a short-term shift of glucose consumption from glycolysis to the pentose phosphate pathway (PPP) along with an increase in reactive oxygen species (ROS) generation. Overall, we suggest that signaling by endogenous CO stimulates the rapid formation of reduction equivalents (NADPH) via the PPP, and plays an additional role in antioxidant defense, e.g., via feed-forward stimulation of the bilirubin/biliverdin redox cycling system.

On the Respective Roles of Nitric Oxide and Carbon Monoxide in Long-Term Potentiation in the Hippocampus

1999 ◽  
Vol 6 (1) ◽  
pp. 63-76 ◽  
Author(s):  
Min Zhuo ◽  
Jarmo T. Laitinen ◽  
Xiao-Ching Li ◽  
Robert D. Hawkins
Keyword(s):  
Nitric Oxide ◽  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Guanylyl Cyclase ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
No Synthase ◽  
Term Potentiation ◽  
Stimulation Of

Perfusion of hippocampal slices with an inhibitor nitric oxide (NO) synthase blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.

Does endogenous zinc protoporphyrin modulate carbon monoxide formation from heme? Implications for long-term potentiation, memory, and cognitive function

1993 ◽  
Vol 71 (10-11) ◽  
pp. 753-754 ◽  
Author(s):  
Gerald S. Marks ◽  
Kanji Nakatsu ◽  
James F. Brien
Keyword(s):  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Cell Function ◽  
Physiological Role ◽  
Long Term Potentiation ◽  
Biological Properties ◽  
Zinc Protoporphyrin ◽  
Term Potentiation ◽  
Oxygenase Activity

Carbon monoxide, which is formed endogenously from heme catabolism catalyzed by heme oxygenase and shares some of the chemical and biological properties of nitric oxide, may play a similar role as a widespread signal transduction mechanism for the regulation of cell function and communication. Zinc protoporphyrin, an inhibitor of heme oxygenase, prevents induction of long-term potentiation. Zinc protoporphyrin is an endogenous substance and we suggest that it has a physiological role, by modulating heme oxygenase activity and, therefore, formation of carbon monoxide from heme. This in turn would modulate long-term potentiation, memory, and cognitive function.Key words: zinc protoporphyrin, carbon monoxide, heme oxygenase, long-term potentiation.

scholarly journals Effects of acute hypoxia on the energy status and antioxidant defense system in the blood of carp - Cyprinvs carpio L.

2002 ◽  
Vol 54 (1-2) ◽  
pp. 11-18
Author(s):  
Radoslav Zikic ◽  
Andras Stajn ◽  
Sladjan Pavlovic ◽  
Branka Ognjanovic ◽  
Snezana Maletic ◽  
...  
Keyword(s):  
Antioxidant Defense ◽  
Reduced Glutathione ◽  
Acute Hypoxia ◽  
Lipid Peroxide ◽  
Antioxidant Defense System ◽  
Energy Status ◽  
Glutathione S Transferase ◽  
Short Term ◽  
Hypoxic Conditions

The influence of acute hypoxia on glucose, pyruvate, lipid peroxide (LP) reduced glutathione (GSH) concentrations and lactate level in the whole blood of carp (Cyprinus carpio L) under aquarium conditions were studied. The activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), the concentrations of ATP and ADP and ATP/ADP ratio in the red blood cells (RBCs) were analyzed. Glutathione-S-transferase (GST) activity was determined in the plasma. Our experiments showed that short-term and long-term hypoxia causes significant changes of all examined haema-tological parameters. Increased concentration of LP and increased SOD CAT and GST activities, as well as a decreased GSH-Px activity showed that under hypoxic conditions oxidative stress and RBCs damage were produced.

Dual role of heme oxygenase in epithelial cell injury: Contrasting effects of short-term and long-term exposure to oxidant stress

1996 ◽  
Vol 128 (3) ◽  
pp. 290-296 ◽  
Author(s):  
Jean-Louis Da Silva ◽  
Tomoyuki Morishita ◽  
Bruno Escalante ◽  
Robert Staudinger ◽  
George Drummond ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Heme Oxygenase ◽  
Cell Injury ◽  
Oxidant Stress ◽  
Dual Role ◽  
Short Term ◽  
Epithelial Cell Injury

Inhibitors of the heme oxygenase – carbon monoxide system: on the doorstep of the clinic?

2008 ◽  
Vol 86 (9) ◽  
pp. 577-599 ◽  
Author(s):  
Robert T. Kinobe ◽  
Ryan A. Dercho ◽  
Kanji Nakatsu
Keyword(s):  
Carbon Monoxide ◽  
Physicochemical Properties ◽  
Heme Oxygenase ◽  
Neurodegenerative Disorders ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Heme Oxygenases ◽  
The Past ◽  
Potential Applications

The past decade has seen substantial developments in our understanding of the physiology, pathology, and pharmacology of heme oxygenases (HO), to the point that investigators in the field are beginning to contemplate therapies based on administration of HO agonists or HO inhibitors. A significant amount of our current knowledge is based on the judicious application of metalloporphyrin inhibitors of HO, despite their limitations of selectivity. Recently, imidazole-based compounds have been identified as potent and more selective HO inhibitors. This ‘next generation’ of HO inhibitors offers a number of desirable characteristics, including isozyme selectivity, negligible effects on HO protein expression, and physicochemical properties favourable for in vivo distribution. Some of the applications of HO inhibitors that have been suggested are treatment of hyperbilirubinemia, neurodegenerative disorders, certain types of cancer, and bacterial and fungal infections. In this review, we address various approaches to altering HO activity with a focus on the potential applications of second-generation inhibitors of HO.

scholarly journals On the Respective Roles of Nitric Oxide and Carbon Monoxide in Long-Term Potentiation in the Hippocampus

1998 ◽  
Vol 5 (6) ◽  
pp. 467-480
Author(s):  
Min Zhuo ◽  
Jarmo T. Laitinen ◽  
Xiao-Ching Li ◽  
Robert D. Hawkins
Keyword(s):  
Nitric Oxide ◽  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Guanylyl Cyclase ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
No Synthase ◽  
Term Potentiation ◽  
Stimulation Of

Perfusion of hippocampal slices with an inhibitor of nitric oxide (NO) synthase-blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.

scholarly journals Pre-Diabetes is a Predictor of Short-Term Poor Outcomes After Acute Ischemic Stroke Using iv Thrombolysis.: Pre-Diabetes Might Be an Alienated Area From Medical Attention Before Stroke Onset

2020 ◽  
Author(s):  
Byoung-Gwon Kim ◽  
Ga-Yeon Kim ◽  
Jae-Kwan Cha
Keyword(s):  
Ischemic Stroke ◽  
Glucose Metabolism ◽  
Functional Outcomes ◽  
Hospital Death ◽  
Long Term Outcomes ◽  
Short Term ◽  
Normal Glucose ◽  
Poor Outcomes ◽  
Hba1c Levels

Abstract Backgrounds: Pre-diabetes is an intermediate state between normal glucose metabolism and diabetes. Recent studies suggest that the presence of pre-diabetes is associated with poor outcomes after AIS. However, the results have been controversial. This study examines whether pre-diabetes influences the patients' short and long-term outcomes for AIS using IV thrombolysis. Methods: We enrolled 661 AIS patients with IV thrombolysis. Based on the 2010 ADA guidelines, patients were classified as pre-diabetes, with HbA1c levels of 5.7%–6.4%; diabetes, HbA1c levels more than 6.5%; and NGM (normal glucose metabolism), with HbA1c levels less than 5.7%. We investigated short-term outcomes, including early neurologic deterioration (END), in-hospital death, and poor functional outcomes (mRS>2) at 90days. As for long-term outcomes, poor functional outcomes were measured at 1 year. Results: Of the 661 AIS patients treated with IV thrombolysis, 197 patients (29.8%) were diagnosed with pre-diabetes, and 210 (31.8%) were diagnosed with diabetes. In a multivariate analysis, pre-diabetes was an independent predictor for END (OR=2.02; 95% CI 1.12-3.62; p=0.02) and in-hospital death (OR=3.12; 95% CI 1.06-9.09; p=0.04). In contrast, diabetes was a significant independent factor for poor long-term outcomes (OR=1.75; 95% CI 1.09-2.78; p=0.02) after correcting confounding factors. Conclusion: Unlike diabetes, pre-diabetes can be an important predictor of short-term outcomes after AIS. However, more detailed research is needed to specify the precise mechanisms by which pre-diabetes affects the prognosis of acute ischemic stroke.

scholarly journals Heme-Oxygenase and Kidney Transplantation: A Potential for Target Therapy?

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 840
Author(s):  
Daniela Corona ◽  
Burcin Ekser ◽  
Rossella Gioco ◽  
Massimo Caruso ◽  
Chiara Schipa ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Heme Oxygenase ◽  
Target Therapy ◽  
Short Term ◽  
Ischemia And Reperfusion Injury ◽  
Stage Renal Disease ◽  
End Stage ◽  
Near Future ◽  
Rate Limiting

Kidney transplantation is a well-established therapy for patients with end-stage renal disease. While a significant improvement of short-term results has been achieved in the short-term, similar results were not reported in the long-term. Heme-oxygenase (HO) is the rate-limiting enzyme in heme catabolism, converting heme to iron, carbon monoxide, and biliverdin. Heme-oxygenase overexpression may be observed in all phases of transplant processes, including brain death, recipient management, and acute and chronic rejection. HO induction has been proved to provide a significant reduction of inflammatory response and a reduction of ischemia and reperfusion injury in organ transplantation, as well as providing a reduction of incidence of acute rejection. In this review, we will summarize data on HO and kidney transplantation, suggesting possible clinical applications in the near future to improve the long-term outcomes.

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