|
1
|
Zhu S, Liu Z, Hu B, Feng Y, Pan G. Nitrite Reductases in Biomedicine: From Natural Enzymes to Artificial Mimics. RESEARCH (WASHINGTON, D.C.) 2025; 8:0710. [PMID: 40438154 PMCID: PMC12117333 DOI: 10.34133/research.0710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 04/26/2025] [Accepted: 04/28/2025] [Indexed: 06/01/2025]
Abstract
Nitrite reductases (NiRs) are natural enzymes that facilitate the reduction of nitrite. They are essential for the microbial nitrogen cycle and play a vital role in regulating numerous physiological and pathological processes associated with nitric oxide (NO) in living organisms. By the merits of protein engineering, a variety of artificial NiR mimics have been developed. These include traditional artificial proteins, metal-azacycle complexes, and nanozymes such as metal, metal oxide/sulfide nanoparticles, metal-organic frameworks, bioinorganic nanohybrids, and advanced single-atom nanozymes. This development marks an important milestone in broadening the application of enzyme-like catalytic nitrite reduction across various fields, such as biomedicine, biosensing, food science, and environmental science. In this review, we first outline the different types of NiRs, along with their active center structures and catalytic mechanisms, drawing from recent research and discoveries. We then classify the reported NiR mimic materials, discussing their active center structures and enzyme-like catalytic mechanisms. Additionally, we explore the potential future applications and challenges facing NiR mimics in the field of biomedicine.
Collapse
Affiliation(s)
- Sai Zhu
- Institute for Advanced Materials, School of Materials Science and Engineering,
Jiangsu University, Zhenjiang 212013, China
| | - Zhengbiao Liu
- Department of Orthopedics,
Suzhou Industrial Park Xinghu Hospital, Suzhou, Jiangsu 215000, China
| | - Bo Hu
- Jilin Provincial Key Laboratory of Western Jilin’s Clean Energy,
Baicheng Normal University, Baicheng 137000, China
| | - Yonghai Feng
- Institute for Advanced Materials, School of Materials Science and Engineering,
Jiangsu University, Zhenjiang 212013, China
| | - Guoqing Pan
- Institute for Advanced Materials, School of Materials Science and Engineering,
Jiangsu University, Zhenjiang 212013, China
| |
Collapse
|
|
2
|
Ascenzi P, De Simone G, Zingale GA, Coletta M. Nitrite binding to myoglobin and hemoglobin: Reactivity and structural aspects. J Inorg Biochem 2025; 265:112829. [PMID: 39854981 DOI: 10.1016/j.jinorgbio.2025.112829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/07/2025] [Accepted: 01/08/2025] [Indexed: 01/27/2025]
Abstract
Nitrite (NO2-) interacts with myoglobin (Mb) and hemoglobin (Hb) behaving as a ligand of both the ferrous (i.e., Mb(II) and Hb(II)) and ferric (i.e., Mb(III) and Hb(III)) forms. However, while the binding to the Fe(III) species corresponds to the formation of a stable complex (i.e., Mb(III)-NO2- and Hb(III)-NO2-), in the case of the ferrous forms the reaction proceeds with a nitrite reductase redox process, leading to the oxidation of the heme-protein with the reduction of NO2- to NO. This event is of the utmost importance for the rapid production of NO in vivo in the blood stream and in striated muscles, being crucial for the regulation of the blood flow, and thus for O2 supply to poorly oxygenated tissues, such as the eye's retina. Further, NO2- interacts with Mb(II)-O2 and Hb(II)-O2, inducing their oxidation with a complex mechanism, which has been only partially elucidated. Mb and Hb form the complex with NO2- through the O-nitrito binding mode (i.e., Fe-ONO-), which is regulated by residues paving the heme distal side; thus, in a site-directed mutant, where HisE7 is substituted by Val, the interaction occurs in the N-nitro binding mode (i.e., Fe-N(O)O-), like in most other heme-proteins. The structure-function relationships of the interaction of NO2- with both ferric and ferrous forms of Mb and Hb are discussed here.
Collapse
Affiliation(s)
- Paolo Ascenzi
- Accademia Nazionale dei Lincei, Via della Lungara 10, 00165 Roma, Italy; Dipartimento di Scienze, Università Roma Tre, Viale Guglielmo Marconi 446, 00146 Roma, Italy.
| | - Giovanna De Simone
- Dipartimento di Scienze, Università Roma Tre, Viale Guglielmo Marconi 446, 00146 Roma, Italy
| | | | | |
Collapse
|
|
3
|
Chen LY, Chen PL, Jiang ST, Lee HL, Liu YY, Chueh A, Lin JH, Chen CG, Hung CL, Hsu K. Increased Anion Exchanger-1 (Band 3) on the Red Blood Cell Membrane Accelerates Scavenging of Nitric Oxide Metabolites and Predisposes Hypertension Risks. FUNCTION 2025; 6:zqae052. [PMID: 39656872 PMCID: PMC11815584 DOI: 10.1093/function/zqae052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 10/07/2024] [Accepted: 12/02/2024] [Indexed: 12/17/2024] Open
Abstract
The erythrocyte membrane is highly specialized with ∼1 million anion exchanger-1 (AE1) per cell for rapid membrane permeation of HCO3-(aq), as most blood CO2(g) is carried in this hydrated anionic form. People with the GP.Mur blood type have more AE1 on their erythrocyte membrane, and they excrete CO2(g) more efficiently. Unexpectedly, GP.Mur/increased AE1 is also associated with higher blood pressure (BP). To solve this, we knocked the human GYP.Mur gene into C57BL/6J mice at 3'-UTR of GYPA to generate GPMur knock-in (KI) mice. KI of human GYP.Mur increased murine AE1 expression on the red blood cells (RBC). GPMur KI mice were naturally hypertensive, with normal kidney functions and lipid profiles. Blood NO3- [the stable nitric oxide (NO) reservoir] was significantly lower in the GPMur mice. GPMur KI also accelerated AE1-mediated NO2- influx into the RBCs and intraerythrocytic NO2-/NO processing. From tests with different categories of antihypertensives, hypertension in GPMur mice responded best to direct arterial vasodilator hydralazine, suggesting that vasodilator deficiency is the leading cause of "GPMur/AE1-triggered hypertension." In conclusion, we showed that GPMur/increased AE1 predisposed hypertension risks. Mechanistically, higher AE1 expression increased RBC membrane permeability for NO2- and consequently accelerated erythroid NO2-/NO metabolism; this is associated with lower NO bioavailability and higher BP. As hypertension affects a quarter of the world population and GP.Mur is a common Southeast Asian (SEA) blood type, this work may serve as a primer for "GPMur (biomarker)-based" therapeutic development for hypertension.
Collapse
Affiliation(s)
- Li-Yang Chen
- The Laboratory of Immunogenetics, Department of Medical Research, MacKay Memorial Hospital, Tamsui, New Taipei City 251020, Taiwan
| | - Pin-Lung Chen
- The Laboratory of Immunogenetics, Department of Medical Research, MacKay Memorial Hospital, Tamsui, New Taipei City 251020, Taiwan
| | - Si-Tse Jiang
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei 106214, Taiwan
| | - Hui-Lin Lee
- The Laboratory of Immunogenetics, Department of Medical Research, MacKay Memorial Hospital, Tamsui, New Taipei City 251020, Taiwan
| | - Yen-Yu Liu
- Department of Critical Care Medicine, MacKay Memorial Hospital, Tamsui, New Taipei City 251020, Taiwan
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City 252005, Taiwan
- Division of Cardiology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104217, Taiwan
| | - Alysa Chueh
- The Laboratory of Immunogenetics, Department of Medical Research, MacKay Memorial Hospital, Tamsui, New Taipei City 251020, Taiwan
| | - Jing-Heng Lin
- The Laboratory of Immunogenetics, Department of Medical Research, MacKay Memorial Hospital, Tamsui, New Taipei City 251020, Taiwan
| | - Caleb G Chen
- Department of Hematology, MacKay Memorial Hospital, Taipei 104217, Taiwan
- Department of Hematology, GCRC Laboratory, Mackay Memorial Hospital, New Taipei City 251020, Taiwan
- Institute of Molecular Medicine, National Tsing-Hua University, Hsin-Chu 300044, Taiwan
- MacKay Junior College of Medicine, Nursing, and Management, New Taipei City 252005, Taiwan
| | - Chung-Lieh Hung
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City 252005, Taiwan
- Division of Cardiology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104217, Taiwan
| | - Kate Hsu
- The Laboratory of Immunogenetics, Department of Medical Research, MacKay Memorial Hospital, Tamsui, New Taipei City 251020, Taiwan
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City 252005, Taiwan
- MacKay Junior College of Medicine, Nursing, and Management, New Taipei City 252005, Taiwan
| |
Collapse
|
|
4
|
Galinato MGI, Wyant C, Lombardo AL, MacIsaac EK, Rios-Martinez DA, Kimrey CD, Castro AA. Generating globin-like reactivities in [human serum albumin-Fe II(heme)] complex through N-donor ligand addition. J Inorg Biochem 2025; 262:112743. [PMID: 39357192 DOI: 10.1016/j.jinorgbio.2024.112743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/11/2024] [Accepted: 09/20/2024] [Indexed: 10/04/2024]
Abstract
Human serum albumin (HSA) has a strong binding affinity for heme b, forming a complex in a 1:1 ratio with the co-factor ([HSA-FeIIIheme]). This system displays spectroscopic and functional properties comparable to globins when chemical derivatives mimicking them are incorporated into the protein matrix. The aim of this study is to generate globin-like systems using [HSA-FeIIIheme] as a protein template and binding N-donor ligands (imidazole, Im; and 1-methylimidazole, 1-MeIm) to construct artificial [HSA-Fe(heme)-(N-donor)] complexes. Their electronic structure and binding thermodynamics are investigated using UV-vis and (synchronous) fluorescence spectroscopies, while ligand-protein interactions are visualized using docking simulations. The imidazole derivatives have a strong affinity for [HSA-FeIIIheme] (K ∼ 104-106), where the spontaneous binding of Im and 1-MeIm are dominated by entropic and enthalpic effects, respectively. The reduced form of the [HSA-Fe(heme)-(N-donor)] complexes demonstrate nitrite reductase (NiR) activity similar to that observed in globins, but with significant differences in their rates. [HSA-FeIIheme-(1-MeIm)] reduces nitrite ∼4× faster than the Im analogue, and ∼ 30× faster than myoglobin (Mb). The enhanced NiR activity of [HSA-FeIIheme-(1-MeIm)] is a cumulative effect of several factors including a slightly expanded and more optimal heme binding pocket, nearby residues as possible proton sources, and a H-bonding interaction between 1-MeIm and residues Arg160 and Lys181 that may have a long-distance influence on the heme π electron density.
Collapse
Affiliation(s)
- Mary Grace I Galinato
- Department of Chemistry & Physics, Jacksonville University, 2800 University Blvd N, Jacksonville, FL 32211, United States; School of Science - Chemistry, Penn State Behrend, 4205 College Dr., Erie, PA 16563, United States.
| | - Christopher Wyant
- School of Science - Chemistry, Penn State Behrend, 4205 College Dr., Erie, PA 16563, United States
| | - Ashley L Lombardo
- School of Science - Chemistry, Penn State Behrend, 4205 College Dr., Erie, PA 16563, United States
| | - Ethan K MacIsaac
- Department of Chemistry & Physics, Jacksonville University, 2800 University Blvd N, Jacksonville, FL 32211, United States
| | - Daniella A Rios-Martinez
- School of Science - Chemistry, Penn State Behrend, 4205 College Dr., Erie, PA 16563, United States
| | - Christopher D Kimrey
- School of Science - Chemistry, Penn State Behrend, 4205 College Dr., Erie, PA 16563, United States
| | - Alexandra Alfonso Castro
- School of Science - Chemistry, Penn State Behrend, 4205 College Dr., Erie, PA 16563, United States
| |
Collapse
|
|
5
|
Poudel L, Alipour E, Suriany S, Liu H, Baker SR, Karunarathna T, George A, Detterich J, Kim-Shapiro DB. Nitrosyl hemoglobin formation from nitrite in normal and sickle blood. Free Radic Biol Med 2024; 225:316-322. [PMID: 39389210 PMCID: PMC11624053 DOI: 10.1016/j.freeradbiomed.2024.10.271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 08/29/2024] [Accepted: 10/07/2024] [Indexed: 10/12/2024]
Abstract
Sickle cell anemia is caused by a single mutation in the gene encoding the beta subunit of hemoglobin. Due to this mutation, sickle cell hemoglobin (HbS) polymerizes under hypoxic conditions, decreasing red blood cell deformability and leading to multiple pathological effects that cause substantial morbidity and mortality. Several pre-clinical and human studies have demonstrated that the anion nitrite has potential therapeutic benefits for patients with sickle cell disease. Nitrite is reduced to nitric oxide (NO) by deoxygenated hemoglobin contributing to vasodilation, decreasing platelet activation, decreasing cellular adhesion to activated endothelium, and decreasing red cell hemolysis; all of which could ameliorate patient morbidities. Previous work on extracellular hemoglobin has shown that solution phase HbS reduces nitrite to NO faster than normal adult hemoglobin (HbA), while polymerized HbS reduces nitrite slower than HbA. In this work, we compared the rate of nitrite reduction to NO measured by the formation of nitrosyl hemoglobin in sickle and normal red blood cells at varying hemoglobin oxygen saturations. We found the overall rate of nitrite reduction between normal and sickle red blood cells was similar and confirmed this result under partially oxygenated conditions, but normal red blood cells reduced nitrite faster than sickle red blood cells under anoxia where HbS polymerization is maximal. These results are consistent with previous work using extracellular hemoglobin where the rate of reduction by solution phase HbS makes up for the slower reduction by polymer phase HbS under partially oxygenated conditions, but the polymer phase kinetics dominates in the complete absence of oxygen.
Collapse
Affiliation(s)
- Laxman Poudel
- Department of Physics, Wake Forest University, Winston-Salem, NC, 27109, USA
| | - Elmira Alipour
- Department of Physics, Wake Forest University, Winston-Salem, NC, 27109, USA
| | - Silvie Suriany
- Division of Cardiology, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA
| | - Honglei Liu
- Division of Cardiology, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA
| | - Stephen R Baker
- Department of Physics, Wake Forest University, Winston-Salem, NC, 27109, USA
| | | | - Alex George
- Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Jon Detterich
- Division of Cardiology, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA; Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
| | | |
Collapse
|
|
6
|
Bailey DM, Bain AR, Hoiland RL, Barak OF, Drvis I, Stacey BS, Iannetelli A, Davison GW, Dahl RH, Berg RMG, MacLeod DB, Dujic Z, Ainslie PN. Severe hypoxaemic hypercapnia compounds cerebral oxidative-nitrosative stress during extreme apnoea: Implications for cerebral bioenergetic function. J Physiol 2024; 602:5659-5684. [PMID: 38348606 DOI: 10.1113/jp285555] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 01/16/2024] [Indexed: 11/01/2024] Open
Abstract
We examined the extent to which apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end-apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015-0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative-nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative-nitrosative stress. KEY POINTS: Local sampling of blood across the cerebral circulation in ultra-elite apnoeists determined the extent to which severe end-apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical-mediated nitric oxide bioavailability and global cerebral bioenergetic function. Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative-nitrosative stress. The apnoea-induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose. Cerebral oxidative-nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea-induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia. This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production.
Collapse
Affiliation(s)
- Damian M Bailey
- Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK
| | - Anthony R Bain
- Department of Kinesiology, Faculty of Human Kinetics, University of Windsor, Windsor, ON, Canada
| | - Ryan L Hoiland
- Department of Anaesthesiology, Pharmacology and Therapeutics, Vancouver General Hospital, West 12th Avenue, University of British Columbia, Vancouver, BC, Canada
- Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Otto F Barak
- Department of Integrative Physiology, School of Medicine, University of Split, Split, Croatia
- Department of Sports Medicine, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Ivan Drvis
- School of Kinesiology, University of Zagreb, Zagreb, Croatia
| | - Benjamin S Stacey
- Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK
| | - Angelo Iannetelli
- Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK
| | - Gareth W Davison
- Department of Exercise Biochemistry and Physiology, Sport and Exercise Science Research Institute, Ulster University Belfast, United Kingdom of Great Britain and Northern Ireland, Ulster, UK
| | - Rasmus H Dahl
- Department of Radiology, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Ronan M G Berg
- Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK
- Department of Biomedical Sciences, University of Copenhagen, Denmark
| | - David B MacLeod
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Zeljko Dujic
- Department of Integrative Physiology, School of Medicine, University of Split, Split, Croatia
| | - Philip N Ainslie
- Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK
- School of Health and Exercise Sciences, Faculty of Health and Social Development, Center for Heart Lung and Vascular Health, University of British Columbia, Kelowna, BC, Canada
| |
Collapse
|
|
7
|
Carlström M, Weitzberg E, Lundberg JO. Nitric Oxide Signaling and Regulation in the Cardiovascular System: Recent Advances. Pharmacol Rev 2024; 76:1038-1062. [PMID: 38866562 DOI: 10.1124/pharmrev.124.001060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/30/2024] [Accepted: 05/29/2024] [Indexed: 06/14/2024] Open
Abstract
Nitric oxide (NO) from endothelial NO synthase importantly contributes to vascular homeostasis. Reduced NO production or increased scavenging during disease conditions with oxidative stress contribute to endothelial dysfunction and NO deficiency. In addition to the classical enzymatic NO synthases (NOS) system, NO can also be generated via the nitrate-nitrite-NO pathway. Dietary and pharmacological approaches aimed at increasing NO bioactivity, especially in the cardiovascular system, have been the focus of much research since the discovery of this small gaseous signaling molecule. Despite wide appreciation of the biological role of NOS/NO signaling, questions still remain about the chemical nature of NOS-derived bioactivity. Recent studies show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase, and directly activate the soluble guanylyl cyclase-cGMP-protein kinase G pathway without intermediacy of free NO. Moreover, interaction between red blood cells and the endothelium in the regulation of vascular NO homeostasis have gained much attention, especially in conditions with cardiometabolic disease. In this review we discuss both classical and nonclassical pathways for NO generation in the cardiovascular system and how these can be modulated for therapeutic purposes. SIGNIFICANCE STATEMENT: After four decades of intensive research, questions persist about the transduction and control of nitric oxide (NO) synthase bioactivity. Here we discuss NO signaling in cardiovascular health and disease, highlighting new findings, such as the important role of red blood cells in cardiovascular NO homeostasis. Nonclassical signaling modes, like the nitrate-nitrite-NO pathway, and therapeutic opportunities related to the NO system are discussed. Existing and potential pharmacological treatments/strategies, as well as dietary components influencing NO generation and signaling are covered.
Collapse
Affiliation(s)
- Mattias Carlström
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (M.C., E.W., J.O.L.); and Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden (E.W.)
| | - Eddie Weitzberg
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (M.C., E.W., J.O.L.); and Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden (E.W.)
| | - Jon O Lundberg
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (M.C., E.W., J.O.L.); and Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden (E.W.)
| |
Collapse
|
|
8
|
Fenuta AM, Drouin PJ, Kohoko ZIN, Lynn MJT, Tschakovsky ME. Influence of acute dietary nitrate supplementation on oxygen delivery/consumption and critical impulse during maximal effort forearm exercise in males: a randomized crossover trial. Appl Physiol Nutr Metab 2024; 49:1184-1201. [PMID: 38728747 DOI: 10.1139/apnm-2023-0606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2024]
Abstract
Beetroot juice supplementation (BRJ) should increase nitric oxide bioavailability under conditions of muscle deoxygenation and acidosis that are a normal consequence of the maximal effort exercise test used to identify forearm critical impulse. We hypothesized BRJ would improve oxygen delivery:demand matching and forearm critical impulse performance. Healthy males (20.8 ± 2.4 years) participated in a randomized crossover trial between October 2017 and May 2018 (Queen's University, Kingston, ON). Participants completed 10 min of rhythmic maximal effort forearm handgrip exercise 2.5 h post placebo (PL) vs. BRJ (9 completed PL/BRJ vs. 4 completed BRJ/PL) within a 2 week period. Data are presented as mean ± SD. There was a main effect of drink (PL > BRJ) for oxygen extraction (P = 0.033, ηp2 = 0.351) and oxygen consumption/force (P = 0.017, ηp2 = 0.417). There was a drink × time interaction (PL > BRJ) for oxygen consumption/force (P = 0.035, ηp2 = 0.216) between 75 and 360 s (1.25-6 min) from exercise onset. BRJ did not influence oxygen delivery (P = 0.953, ηp2 = 0.000), oxygen consumption (P = 0.064, ηp2 = 0.278), metabolites ((lactate) (P = 0.196, ηp2 = 0.135), pH (P = 0.759, ηp2 = 0.008)) or power-duration performance parameters (critical impulse (P = 0.379, d = 0.253), W' (P = 0.733, d = 0.097)). BRJ during all-out handgrip exercise does not influence oxygen delivery or exercise performance. Oxygen cost of contraction with BRJ is reduced as contraction impulse is declining during maximal effort exercise resulting in less oxygen extraction.
Collapse
Affiliation(s)
- Alyssa M Fenuta
- School of Kinesiology and Health Studies, Queen's University, Kingston, ON, Canada
| | - Patrick J Drouin
- School of Kinesiology and Health Studies, Queen's University, Kingston, ON, Canada
| | - Zach I N Kohoko
- School of Kinesiology and Health Studies, Queen's University, Kingston, ON, Canada
| | - Mytchel J T Lynn
- School of Kinesiology and Health Studies, Queen's University, Kingston, ON, Canada
| | | |
Collapse
|
|
9
|
Pereira DA, Calmasini FB, Costa FF, Burnett AL, Silva FH. Nitric Oxide Resistance in Priapism Associated with Sickle Cell Disease: Mechanisms, Therapeutic Challenges, and Future Directions. J Pharmacol Exp Ther 2024; 390:203-212. [PMID: 38262744 DOI: 10.1124/jpet.123.001962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/07/2023] [Accepted: 01/05/2024] [Indexed: 01/25/2024] Open
Abstract
Patients with sickle cell disease (SCD) display priapism, a prolonged penile erection in the absence of sexual arousal. The current pharmacological treatments for SCD-associated priapism are limited and focused on acute interventions rather than prevention. Thus, there is an urgent need for new drug targets and preventive pharmacological therapies for this condition. This review focuses on the molecular mechanisms linked to the dysfunction of the NO-cyclic guanosine monophosphate (cGMP)-phosphodiesterase type 5 (PDE5) pathway implicated in SCD-associated priapism. In murine models of SCD, reduced nitric oxide (NO)-cGMP bioavailability in the corpus cavernosum is associated with elevated plasma hemoglobin levels, increased reactive oxygen species levels that inactive NO, and testosterone deficiency that leads to endothelial nitric oxide synthase downregulation. We discuss the consequences of the reduced cGMP-dependent PDE5 activity in response to these molecular changes, highlighting it as the primary pathophysiological mechanism leading to excessive corpus cavernosum relaxation, culminating in priapism. We also further discuss the impact of intravascular hemolysis on therapeutic approaches, present current pharmacological strategies targeting the NO-cGMP-PDE5 pathway in the penis, and identify potential pharmacological targets for future priapism therapies. In men with SCD and priapism, PDE5 inhibitor therapy and testosterone replacement have shown promising results. Recent preclinical research reported the beneficial effect of treatment with haptoglobin and NO donors. SIGNIFICANCE STATEMENT: This review discusses the molecular changes that reduce NO-cGMP bioavailability in the penis in SCD and highlights pharmacological targets and therapeutic strategies for the treatment of priapism, including PDE5 inhibitors, hormonal modulators, NO donors, hydroxyurea, soluble guanylate cyclase stimulators, haptoglobin, hemopexin, and antioxidants.
Collapse
Affiliation(s)
- Dalila Andrade Pereira
- Laboratory of Pharmacology, São Francisco University Medical School, Bragança Paulista, SP, Brazil (D.A.P., F.H.S.); Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil (F.B.C.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.F.C.); and The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland (A.L.B.)
| | - Fabiano Beraldi Calmasini
- Laboratory of Pharmacology, São Francisco University Medical School, Bragança Paulista, SP, Brazil (D.A.P., F.H.S.); Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil (F.B.C.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.F.C.); and The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland (A.L.B.)
| | - Fernando Ferreira Costa
- Laboratory of Pharmacology, São Francisco University Medical School, Bragança Paulista, SP, Brazil (D.A.P., F.H.S.); Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil (F.B.C.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.F.C.); and The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland (A.L.B.)
| | - Arthur L Burnett
- Laboratory of Pharmacology, São Francisco University Medical School, Bragança Paulista, SP, Brazil (D.A.P., F.H.S.); Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil (F.B.C.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.F.C.); and The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland (A.L.B.)
| | - Fábio Henrique Silva
- Laboratory of Pharmacology, São Francisco University Medical School, Bragança Paulista, SP, Brazil (D.A.P., F.H.S.); Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil (F.B.C.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.F.C.); and The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland (A.L.B.)
| |
Collapse
|
|
10
|
Jansen-van Vuuren RD, Liu S, Miah MAJ, Cerkovnik J, Košmrlj J, Snieckus V. The Versatile and Strategic O-Carbamate Directed Metalation Group in the Synthesis of Aromatic Molecules: An Update. Chem Rev 2024; 124:7731-7828. [PMID: 38864673 PMCID: PMC11212060 DOI: 10.1021/acs.chemrev.3c00923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 04/26/2024] [Accepted: 05/08/2024] [Indexed: 06/13/2024]
Abstract
The aryl O-carbamate (ArOAm) group is among the strongest of the directed metalation groups (DMGs) in directed ortho metalation (DoM) chemistry, especially in the form Ar-OCONEt2. Since the last comprehensive review of metalation chemistry involving ArOAms (published more than 30 years ago), the field has expanded significantly. For example, it now encompasses new substrates, solvent systems, and metalating agents, while conditions have been developed enabling metalation of ArOAm to be conducted in a green and sustainable manner. The ArOAm group has also proven to be effective in the anionic ortho-Fries (AoF) rearrangement, Directed remote metalation (DreM), iterative DoM sequences, and DoM-halogen dance (HalD) synthetic strategies and has been transformed into a diverse range of functionalities and coupled with various groups through a range of cross-coupling (CC) strategies. Of ultimate value, the ArOAm group has demonstrated utility in the synthesis of a diverse range of bioactive and polycyclic aromatic compounds for various applications.
Collapse
Affiliation(s)
- Ross D. Jansen-van Vuuren
- Department
of Chemistry, Queen’s University, Chernoff Hall, 9 Bader Lane, Kingston, Ontario K7K 2N1, Canada
- Faculty
of Chemistry and Chemical Technology, University
of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
| | - Susana Liu
- Department
of Chemistry, Queen’s University, Chernoff Hall, 9 Bader Lane, Kingston, Ontario K7K 2N1, Canada
| | - M. A. Jalil Miah
- Department
of Chemistry, Rajshahi University, Rajshahi-6205, Bangladesh
| | - Janez Cerkovnik
- Faculty
of Chemistry and Chemical Technology, University
of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
| | - Janez Košmrlj
- Faculty
of Chemistry and Chemical Technology, University
of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
| | - Victor Snieckus
- Department
of Chemistry, Queen’s University, Chernoff Hall, 9 Bader Lane, Kingston, Ontario K7K 2N1, Canada
| |
Collapse
|
|
11
|
Möller MN, Vitturi DA. The chemical biology of dinitrogen trioxide. REDOX BIOCHEMISTRY AND CHEMISTRY 2024; 8:100026. [PMID: 38957295 PMCID: PMC11218869 DOI: 10.1016/j.rbc.2024.100026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/04/2024]
Abstract
Dinitrogen trioxide (N 2 O 3 ) mediates low-molecular weight and protein S- and N-nitrosation, with recent reports suggesting a role in the formation of nitrating intermediates as well as in nitrite-dependent hypoxic vasodilatation. However, the reactivity ofN 2 O 3 in biological systems results in an extremely short half-life that renders this molecule essentially undetectable by currently available technologies. As a result, evidence for in vivoN 2 O 3 formation derives from the detection of nitrosated products as well as from in vitro kinetic determinations, isotopic labeling studies, and spectroscopic analyses. This review will discuss mechanisms ofN 2 O 3 formation, reactivity and decomposition, as well as address the role of sub-cellular localization as a key determinant of its actions. Finally, evidence will be discussed supporting different roles forN 2 O 3 as a biologically relevant signaling molecule.
Collapse
Affiliation(s)
- Matías N. Möller
- Laboratorio Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Darío A. Vitturi
- Department of Pathology. University of Alabama at Birmingham, Birmingham, AL, USA
| |
Collapse
|
|
12
|
Anastasiadi AT, Arvaniti VZ, Hudson KE, Kriebardis AG, Stathopoulos C, D’Alessandro A, Spitalnik SL, Tzounakas VL. Exploring unconventional attributes of red blood cells and their potential applications in biomedicine. Protein Cell 2024; 15:315-330. [PMID: 38270470 PMCID: PMC11074998 DOI: 10.1093/procel/pwae001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 01/08/2024] [Indexed: 01/26/2024] Open
Affiliation(s)
- Alkmini T Anastasiadi
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece
| | - Vasiliki-Zoi Arvaniti
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece
| | - Krystalyn E Hudson
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York City, NY 10032, USA
| | - Anastasios G Kriebardis
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, School of Health & Caring Sciences, University of West Attica (UniWA), 12243 Egaleo, Greece
| | | | - Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, 13001 Aurora, CO, USA
| | - Steven L Spitalnik
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York City, NY 10032, USA
| | - Vassilis L Tzounakas
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece
| |
Collapse
|
|
13
|
Fenuta AM, Drouin PJ, Kohoko ZIN, Lynn MJT, Tschakovsky ME. Influence of acute dietary nitrate supplementation on oxygen delivery/consumption and limit of tolerance during progressive forearm exercise in men: a randomized crossover trial. Appl Physiol Nutr Metab 2024; 49:635-648. [PMID: 38190654 DOI: 10.1139/apnm-2023-0236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
Beetroot juice (BRJ) supplementation increases nitric oxide bioavailability with hypoxia and acidosis, characteristics of high-intensity exercise. We investigated whether BRJ improved forearm oxygen delivery:demand matching in an intensity-dependent manner. Healthy men (21 ± 2.5 years) participated in a randomized crossover trial between October 2017 and May 2018 (Queen's University, Kingston, ON, Canada). Participants completed a forearm incremental exercise test to limit of tolerance (IET-LOT) 2.5 h post placebo (PL) versus BRJ (2 completed PL/BRJ vs. 9 completed BRJ/PL) within a 2-week period. Data are presented as mean ± standard deviation. There was a significant main effect of drink (PL < BRJ; P = 0.042, ηp2 = 0.385) and drink × intensity interaction for arteriovenous oxygen difference (PL < BRJ; P = 0.03; ηp2= 0.197; 20%-50% and 90% LOT). BRJ did not influence oxygen delivery (P = 0.893, ηp2 = 0.002), forearm blood flow (P = 0.589, ηp2 = 0.03) (forearm vascular conductance (P = 0.262, ηp2 = 0.124), mean arterial pressure (P = 0.254,ηp2 = 0.128)), oxygen consumption (P = 0.194, ηp2 = 0.179) or LOT (P = 0.432, d = 0.247). In healthy men, BRJ did not improve forearm oxygen delivery (vasodilatory or pressor response) during IET-LOT. Increased arteriovenous oxygen difference at submaximal intensities did not significantly influence oxygen consumption or performance across the entire range of forearm exercise intensities. This study adds to the growing body of evidence that BRJ does not influence small muscle mass blood flow in humans regardless of exercise intensity.
Collapse
Affiliation(s)
- Alyssa M Fenuta
- School of Kinesiology and Health Studies, Queen's University, Kingston, ON, Canada
| | - Patrick J Drouin
- School of Kinesiology and Health Studies, Queen's University, Kingston, ON, Canada
| | - Zach I N Kohoko
- School of Kinesiology and Health Studies, Queen's University, Kingston, ON, Canada
| | - Mytchel J T Lynn
- School of Kinesiology and Health Studies, Queen's University, Kingston, ON, Canada
| | | |
Collapse
|
|
14
|
Stoian I, Iosif L, Gilca M, Vlad A, Tivig I, Bradescu OM, Savu O. L-Arginine-Dependent Nitric Oxide Production in the Blood of Patients with Type 2 Diabetes: A Pilot, Five-Year Prospective Study. Life (Basel) 2024; 14:556. [PMID: 38792578 PMCID: PMC11122261 DOI: 10.3390/life14050556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 04/15/2024] [Accepted: 04/24/2024] [Indexed: 05/26/2024] Open
Abstract
Backgound: Type 2 diabetes mellitus (T2DM) is a major cardiovascular risk factor. Nitric oxide (NO) is one of the many molecules that regulate vascular tone, and red blood cells (RBCs) are known to play an important role in adjusting cardiac function through NO export from RBCs. Our study prospectively investigated the L-arginine (L-arg)-nitric oxide (NO) metabolic pathway in the erythrocytes and plasma of subjects with T2DM. Methods: RBCs and plasma were collected from patients with T2DM (n = 10), at first clinical onset (baseline) and after five years of disease evolution (follow-up). L-arg content was assayed by competitive enzyme-linked immunoassay. Arginase activity and nitrate/nitrite levels were measured using spectrophotometry. Results: When compared to baseline, L-arg content decreased in RBCs and remained similar in the plasma; NO production decreased in RBCs and the plasma; and arginase activity was lower in RBCs and increased in plasma. Conclusions: The L-arg/NO metabolic pathway decreases in the RBCs of patients with T2DM five years after the first clinical onset. The persistent decrease in RBCs' arginase activity fails to compensate for the sustained decrease in RBCs' NO production in the diabetic environment. This pilot study indicates that the NO-RBC pool is depleted during the progression of the disease in the same cohort of T2DM patients.
Collapse
Affiliation(s)
- Irina Stoian
- Department of Functional Sciences I/Biochemistry, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (I.S.); (L.I.); (M.G.)
- IristLabmed SRL, 031235 Bucharest, Romania;
| | - Liviu Iosif
- Department of Functional Sciences I/Biochemistry, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (I.S.); (L.I.); (M.G.)
- IristLabmed SRL, 031235 Bucharest, Romania;
| | - Marilena Gilca
- Department of Functional Sciences I/Biochemistry, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (I.S.); (L.I.); (M.G.)
| | - Adelina Vlad
- Department of Functional Sciences I/Physiology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Ioan Tivig
- IristLabmed SRL, 031235 Bucharest, Romania;
- Biophysics and Cellular Biotechnology Department, Excellence Center for Research in Biophysics and Cellular Biotechnology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Ovidiu Marius Bradescu
- N.C. Paulescu National Institute of Diabetes, Nutrition and Metabolic Diseases, 020475 Bucharest, Romania; (O.M.B.); (O.S.)
| | - Octavian Savu
- N.C. Paulescu National Institute of Diabetes, Nutrition and Metabolic Diseases, 020475 Bucharest, Romania; (O.M.B.); (O.S.)
- Department of Doctoral School, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| |
Collapse
|
|
15
|
Chen PL, Huang KT, Chen LY, Hsu K. Erythroid anion Exchanger-1 (band 3) transports nitrite for nitric oxide metabolism. Free Radic Biol Med 2024; 210:237-245. [PMID: 38042224 DOI: 10.1016/j.freeradbiomed.2023.11.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/23/2023] [Accepted: 11/26/2023] [Indexed: 12/04/2023]
Abstract
Nitrite (NO2-) interacts with hemoglobin (Hb) in various ways to regulate blood flow. During hypoxic vasodilation, nitrite is reduced by deoxyHb to yield nitric oxide (NO). While NO, a hydrophobic gas, could freely diffuse across the cell membrane, how the reactant nitrite anion could permeate through the red blood cell (RBC) membrane remains unclear. We hypothesized that Cl-/HCO3- anion exchanger-1 (AE1; band 3) abundantly embedded in the RBC membrane could transport NO2-, as HCO3- and NO2- exhibit similar hydrated radii. Here, we monitored NO/N2O3 generated from NO2- inside human RBCs by DAF-FM fluorophore. NO2-, not NO3-, increased intraerythrocytic DAF-FM fluorescence. To test the involvement of AE1-mediated transport in intraerythrocytic NO/N2O3 production from nitrite, we lowered Cl- or HCO3- in the RBC-incubating buffer by 20 % and indeed observed slower rise of the DAF-FM fluorescence. Anti-extracellular AE1, but not anti-intracellular AE1 antibodies, reduced the rates of NO formation from nitrite. The AE1 blocker DIDS similarly reduced the rates of NO/N2O3 production from nitrite in a dose-dependent fashion, confirming that nitrite entered RBCs through AE1. Nitrite inside the RBCs reacted with both deoxyHb and oxyHb, as evidenced by 6.1 % decrease in deoxyHb, 14.7 % decrease in oxyHb, and 20.7 % increase in methemoglobin (metHb). Lowering Cl- in the milieu equally delayed metHb production from nitrite-oxyHb and nitrite-deoxyHb reactions. Thus, AE1-mediated NO2- transport facilitates NO2--Hb reactions inside the red cells, supporting NOx metabolism in circulation.
Collapse
Affiliation(s)
- Pin-Lung Chen
- The Laboratory of Immunogenetics, Department of Medical Research, MacKay Memorial Hospital, Tamsui, New Taipei City, Taiwan
| | - Kuang-Tse Huang
- Department of Chemical Engineering, National Chung-Cheng University, Chia-Yi, Taiwan
| | - Li-Yang Chen
- The Laboratory of Immunogenetics, Department of Medical Research, MacKay Memorial Hospital, Tamsui, New Taipei City, Taiwan
| | - Kate Hsu
- The Laboratory of Immunogenetics, Department of Medical Research, MacKay Memorial Hospital, Tamsui, New Taipei City, Taiwan; MacKay Junior College of Medicine, Nursing, and Management, New Taipei City, Taiwan; Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan.
| |
Collapse
|
|
16
|
Akulich NV, Zinchuk VV. Contribution of the gasotransmitter nitric oxide to the structural and functional organization of erythrocytes under conditions of hypoxia/reoxygenation. BIOMEDITSINSKAIA KHIMIIA 2023; 69:315-321. [PMID: 37937434 DOI: 10.18097/pbmc20236905315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
Hypoxia is accompanied by changes in metabolism and cell functioning. Erythrocyte hemoglobin can be involved in adaptation to hypoxia by acting as an oxygen sensor, providing a link between oxygen content and blood circulation. The mechanisms providing this function have not been completely established. The purpose of this study was to evaluate the effect of the gasotransmitter nitric oxide on the structural and functional organization of erythrocytes under conditions of hypoxia/reoxygenation. NO participated in adaptive reactions under hypoxia/reoxygenation conditions by changing hemoglobin conformation, followed by changes in hemoprotein spectral characteristics and hemoglobin affinity to oxygen together with increasing anisocytosis, volume and cell surface. The increase in intracellular NO concentrations under hypoxic conditions was provided by extracellular fluid nitrites. Molsidomine (a NO donor) induced a higher NO increase without involvement of the nitrite reductase mechanism, it caused an increase in the average erythrocyte volume, anisocytosis, and an increase in the cell surface.
Collapse
Affiliation(s)
- N V Akulich
- National Anti-Doping Laboratory, Lyasny, Minsk Region, Belarus
| | - V V Zinchuk
- Grodno State Medical University, Grodno, Belarus
| |
Collapse
|
|
17
|
Reeder BJ. Insights into the function of cytoglobin. Biochem Soc Trans 2023; 51:1907-1919. [PMID: 37721133 PMCID: PMC10657185 DOI: 10.1042/bst20230081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/11/2023] [Accepted: 09/12/2023] [Indexed: 09/19/2023]
Abstract
Since its discovery in 2001, the function of cytoglobin has remained elusive. Through extensive in vitro and in vivo research, a range of potential physiological and pathological mechanisms has emerged for this multifunctional member of the hemoglobin family. Currently, over 200 research publications have examined different aspects of cytoglobin structure, redox chemistry and potential roles in cell signalling pathways. This research is wide ranging, but common themes have emerged throughout the research. This review examines the current structural, biochemical and in vivo knowledge of cytoglobin published over the past two decades. Radical scavenging, nitric oxide homeostasis, lipid binding and oxidation and the role of an intramolecular disulfide bond on the redox chemistry are examined, together with aspects and roles for Cygb in cancer progression and liver fibrosis.
Collapse
Affiliation(s)
- Brandon J Reeder
- School of Life Sciences, University of Essex, Wivenhoe Park, Colchester, Essex, U.K
| |
Collapse
|
|
18
|
Dent MR, DeMartino AW. Nitric oxide and thiols: Chemical biology, signalling paradigms and vascular therapeutic potential. Br J Pharmacol 2023:10.1111/bph.16274. [PMID: 37908126 PMCID: PMC11058123 DOI: 10.1111/bph.16274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 09/18/2023] [Accepted: 10/09/2023] [Indexed: 11/02/2023] Open
Abstract
Nitric oxide (• NO) interactions with biological thiols play crucial, but incompletely determined, roles in vascular signalling and other biological processes. Here, we highlight two recently proposed signalling paradigms: (1) the formation of a vasodilating labile nitrosyl ferrous haem (NO-ferrohaem) facilitated by thiols via thiyl radical generation and (2) polysulfides/persulfides and their interaction with • NO. We also describe the specific (bio)chemical routes in which • NO and thiols react to form S-nitrosothiols, a broad class of small molecules, and protein post-translational modifications that can influence protein function through catalytic site or allosteric structural changes. S-Nitrosothiol formation depends upon cellular conditions, but critically, an appropriate oxidant for either the thiol (yielding a thiyl radical) or • NO (yielding a nitrosonium [NO+ ]-donating species) is required. We examine the roles of these collective • NO/thiol species in vascular signalling and their cardiovascular therapeutic potential.
Collapse
Affiliation(s)
- Matthew R. Dent
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Anthony W. DeMartino
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
19
|
Beale AD, Hayter EA, Crosby P, Valekunja UK, Edgar RS, Chesham JE, Maywood ES, Labeed FH, Reddy AB, Wright KP, Lilley KS, Bechtold DA, Hastings MH, O'Neill JS. Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells. EMBO J 2023; 42:e114164. [PMID: 37554073 PMCID: PMC10548169 DOI: 10.15252/embj.2023114164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/16/2023] [Accepted: 07/16/2023] [Indexed: 08/10/2023] Open
Abstract
Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in mouse and human RBCs cultured in vitro, or taken from humans in vivo, and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via nitric oxide (NO) signalling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.
Collapse
Affiliation(s)
| | - Edward A Hayter
- Centre for Biological Timing, Faculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
| | - Priya Crosby
- MRC Laboratory of Molecular BiologyCambridgeUK
- Present address:
Department of Chemistry and BiochemistryUniversity of California, Santa CruzSanta CruzCAUSA
| | - Utham K Valekunja
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
- Institute for Translational Medicine and Therapeutics, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Rachel S Edgar
- Department of Infectious DiseasesImperial College LondonLondonUK
| | | | | | - Fatima H Labeed
- Faculty of Engineering and Physical SciencesUniversity of SurreyGuildfordUK
| | - Akhilesh B Reddy
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
- Institute for Translational Medicine and Therapeutics, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Kenneth P Wright
- Department of Integrative Physiology, Sleep and Chronobiology LaboratoryUniversity of Colorado BoulderBoulderCOUSA
| | - Kathryn S Lilley
- Cambridge Centre for Proteomics, Department of BiochemistryUniversity of CambridgeCambridgeUK
| | - David A Bechtold
- Centre for Biological Timing, Faculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
| | | | | |
Collapse
|
|
20
|
Hsia CCW. Tissue Perfusion and Diffusion and Cellular Respiration: Transport and Utilization of Oxygen. Semin Respir Crit Care Med 2023; 44:594-611. [PMID: 37541315 DOI: 10.1055/s-0043-1770061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/06/2023]
Abstract
This article provides an overview of the journey of inspired oxygen after its uptake across the alveolar-capillary interface, and the interplay among tissue perfusion, diffusion, and cellular respiration in the transport and utilization of oxygen. The critical interactions between oxygen and its facilitative carriers (hemoglobin in red blood cells and myoglobin in muscle cells), and with other respiratory and vasoactive molecules (carbon dioxide, nitric oxide, and carbon monoxide), are emphasized to illustrate how this versatile system dynamically optimizes regional convective transport and diffusive gas exchange. The rates of reciprocal gas exchange in the lung and the periphery must be well-matched and sufficient for meeting the range of energy demands from rest to maximal stress but not excessive as to become toxic. The mobile red blood cells play a vital role in matching tissue perfusion and gas exchange by dynamically regulating the controlled uptake of oxygen and communicating regional metabolic signals across different organs. Intracellular oxygen diffusion and facilitation via myoglobin into the mitochondria, and utilization via electron transport chain and oxidative phosphorylation, are summarized. Physiological and pathophysiological adaptations are briefly described. Dysfunction of any component across this integrated system affects all other components and elicits corresponding structural and functional adaptation aimed at matching the capacities across the entire system and restoring equilibrium under normal and pathological conditions.
Collapse
Affiliation(s)
- Connie C W Hsia
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| |
Collapse
|
|
21
|
DeMartino AW, Poudel L, Dent MR, Chen X, Xu Q, Gladwin BS, Tejero J, Basu S, Alipour E, Jiang Y, Rose JJ, Gladwin MT, Kim-Shapiro DB. Thiol-catalyzed formation of NO-ferroheme regulates intravascular NO signaling. Nat Chem Biol 2023; 19:1256-1266. [PMID: 37710075 PMCID: PMC10897909 DOI: 10.1038/s41589-023-01413-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 07/27/2023] [Indexed: 09/16/2023]
Abstract
Nitric oxide (NO) is an endogenously produced signaling molecule that regulates blood flow and platelet activation. However, intracellular and intravascular diffusion of NO are limited by scavenging reactions with several hemoproteins, raising questions as to how free NO can signal in hemoprotein-rich environments. We explore the hypothesis that NO can be stabilized as a labile ferrous heme-nitrosyl complex (Fe2+-NO, NO-ferroheme). We observe a reaction between NO, labile ferric heme (Fe3+) and reduced thiols to yield NO-ferroheme and a thiyl radical. This thiol-catalyzed reductive nitrosylation occurs when heme is solubilized in lipophilic environments such as red blood cell membranes or bound to serum albumin. The resulting NO-ferroheme resists oxidative inactivation, is soluble in cell membranes and is transported intravascularly by albumin to promote potent vasodilation. We therefore provide an alternative route for NO delivery from erythrocytes and blood via transfer of NO-ferroheme and activation of apo-soluble guanylyl cyclase.
Collapse
Affiliation(s)
- Anthony W DeMartino
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Laxman Poudel
- Department of Physics, Wake Forest University, Winston-Salem, NC, USA
| | - Matthew R Dent
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Xiukai Chen
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Qinzi Xu
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Brendan S Gladwin
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jesús Tejero
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Swati Basu
- Department of Physics, Wake Forest University, Winston-Salem, NC, USA
- Translational Science Center, Wake Forest University, Winston-Salem, NC, USA
| | - Elmira Alipour
- Department of Physics, Wake Forest University, Winston-Salem, NC, USA
| | - Yiyang Jiang
- Department of Physics, Wake Forest University, Winston-Salem, NC, USA
| | - Jason J Rose
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Mark T Gladwin
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Daniel B Kim-Shapiro
- Department of Physics, Wake Forest University, Winston-Salem, NC, USA.
- Translational Science Center, Wake Forest University, Winston-Salem, NC, USA.
| |
Collapse
|
|
22
|
Aboouf MA, Gorr TA, Hamdy NM, Gassmann M, Thiersch M. Myoglobin in Brown Adipose Tissue: A Multifaceted Player in Thermogenesis. Cells 2023; 12:2240. [PMID: 37759463 PMCID: PMC10526770 DOI: 10.3390/cells12182240] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 09/01/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Brown adipose tissue (BAT) plays an important role in energy homeostasis by generating heat from chemical energy via uncoupled oxidative phosphorylation. Besides its high mitochondrial content and its exclusive expression of the uncoupling protein 1, another key feature of BAT is the high expression of myoglobin (MB), a heme-containing protein that typically binds oxygen, thereby facilitating the diffusion of the gas from cell membranes to mitochondria of muscle cells. In addition, MB also modulates nitric oxide (NO•) pools and can bind C16 and C18 fatty acids, which indicates a role in lipid metabolism. Recent studies in humans and mice implicated MB present in BAT in the regulation of lipid droplet morphology and fatty acid shuttling and composition, as well as mitochondrial oxidative metabolism. These functions suggest that MB plays an essential role in BAT energy metabolism and thermogenesis. In this review, we will discuss in detail the possible physiological roles played by MB in BAT thermogenesis along with the potential underlying molecular mechanisms and focus on the question of how BAT-MB expression is regulated and, in turn, how this globin regulates mitochondrial, lipid, and NO• metabolism. Finally, we present potential MB-mediated approaches to augment energy metabolism, which ultimately could help tackle different metabolic disorders.
Collapse
Affiliation(s)
- Mostafa A. Aboouf
- Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland
- Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Thomas A. Gorr
- Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland
| | - Nadia M. Hamdy
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Max Gassmann
- Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland
- Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland
| | - Markus Thiersch
- Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland
- Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland
| |
Collapse
|
|
23
|
Turilli-Ghisolfi ES, Lualdi M, Fasano M. Ligand-Based Regulation of Dynamics and Reactivity of Hemoproteins. Biomolecules 2023; 13:683. [PMID: 37189430 PMCID: PMC10135655 DOI: 10.3390/biom13040683] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/14/2023] [Accepted: 04/15/2023] [Indexed: 05/17/2023] Open
Abstract
Hemoproteins include several heme-binding proteins with distinct structure and function. The presence of the heme group confers specific reactivity and spectroscopic properties to hemoproteins. In this review, we provide an overview of five families of hemoproteins in terms of dynamics and reactivity. First, we describe how ligands modulate cooperativity and reactivity in globins, such as myoglobin and hemoglobin. Second, we move on to another family of hemoproteins devoted to electron transport, such as cytochromes. Later, we consider heme-based reactivity in hemopexin, the main heme-scavenging protein. Then, we focus on heme-albumin, a chronosteric hemoprotein with peculiar spectroscopic and enzymatic properties. Eventually, we analyze the reactivity and dynamics of the most recently discovered family of hemoproteins, i.e., nitrobindins.
Collapse
Affiliation(s)
| | | | - Mauro Fasano
- Department of Science and High Technology, University of Insubria, 22100 Como, Italy
| |
Collapse
|
|
24
|
De Simone G, di Masi A, Tundo GR, Coletta M, Ascenzi P. Nitrite Reductase Activity of Ferrous Nitrobindins: A Comparative Study. Int J Mol Sci 2023; 24:ijms24076553. [PMID: 37047528 PMCID: PMC10094804 DOI: 10.3390/ijms24076553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/17/2023] [Accepted: 03/20/2023] [Indexed: 04/03/2023] Open
Abstract
Nitrobindins (Nbs) are all-β-barrel heme proteins spanning from bacteria to Homo sapiens. They inactivate reactive nitrogen species by sequestering NO, converting NO to HNO2, and promoting peroxynitrite isomerization to NO3−. Here, the nitrite reductase activity of Nb(II) from Mycobacterium tuberculosis (Mt-Nb(II)), Arabidopsis thaliana (At-Nb(II)), Danio rerio (Dr-Nb(II)), and Homo sapiens (Hs-Nb(II)) is reported. This activity is crucial for the in vivo production of NO, and thus for the regulation of blood pressure, being of the utmost importance for the blood supply to poorly oxygenated tissues, such as the eye retina. At pH 7.3 and 20.0 °C, the values of the second-order rate constants (i.e., kon) for the reduction of NO2− to NO and the concomitant formation of nitrosylated Mt-Nb(II), At-Nb(II), Dr-Nb(II), and Hs-Nb(II) (Nb(II)-NO) were 7.6 M−1 s−1, 9.3 M−1 s−1, 1.4 × 101 M−1 s−1, and 5.8 M−1 s−1, respectively. The values of kon increased linearly with decreasing pH, thus indicating that the NO2−-based conversion of Nb(II) to Nb(II)-NO requires the involvement of one proton. These results represent the first evidence for the NO2 reductase activity of Nbs(II), strongly supporting the view that Nbs are involved in NO metabolism. Interestingly, the nitrite reductase reactivity of all-β-barrel Nbs and of all-α-helical globins (e.g., myoglobin) was very similar despite the very different three-dimensional fold; however, differences between all-α-helical globins and all-β-barrel Nbs suggest that nitrite reductase activity appears to be controlled by distal steric barriers, even though a more complex regulatory mechanism can be also envisaged.
Collapse
Affiliation(s)
| | | | - Grazia R. Tundo
- Dipartimento di Scienze Cliniche e Medicina Traslazionale, Università di Roma Tor Vergata, 00133 Roma, Italy
| | | | - Paolo Ascenzi
- Laboratorio Interdipartimentale di Microscopia Elettronica, Università Roma Tre, 00146 Roma, Italy
| |
Collapse
|
|
25
|
Kulbir, Das S, Devi T, Ghosh S, Chandra Sahoo S, Kumar P. Acid-induced nitrite reduction of nonheme iron(ii)-nitrite: mimicking biological Fe-NiR reactions. Chem Sci 2023; 14:2935-2942. [PMID: 36937601 PMCID: PMC10016336 DOI: 10.1039/d2sc06704h] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/14/2023] [Indexed: 02/25/2023] Open
Abstract
Nitrite reductase (NiR) catalyzes nitrite (NO2 -) to nitric oxide (NO) transformation in the presence of an acid (H+ ions/pH) and serves as a critical step in NO biosynthesis. In addition to the NiR enzyme, NO synthases (NOSs) participate in NO production. The chemistry involved in the catalytic reduction of NO2 -, in the presence of H+, generates NO with a H2O molecule utilizing two H+ + one electron from cytochromes and is believed to be affected by the pH. Here, to understand the effect of H+ ions on NO2 - reduction, we report the acid-induced NO2 - reduction chemistry of a nonheme FeII-nitrito complex, [(12TMC)FeII(NO2 -)]+ (FeII-NO2 -, 2), with variable amounts of H+. FeII-NO2 - upon reaction with one-equiv. of acid (H+) generates [(12TMC)Fe(NO)]2+, {FeNO}7 (3) with H2O2 rather than H2O. However, the amount of H2O2 decreases with increasing equivalents of H+ and entirely disappears when H+ reaches ≅ two-equiv. and shows H2O formation. Furthermore, we have spectroscopically characterized and followed the formation of H2O2 (H+ = one-equiv.) and H2O (H+ ≅ two-equiv.) and explained why bio-driven NiR reactions end with NO and H2O. Mechanistic investigations, using 15N-labeled-15NO2 - and 2H-labeled-CF3SO3D (D+ source), revealed that the N atom in the {Fe14/15NO}7 is derived from the NO2 - ligand and the H atom in H2O or H2O2 is derived from the H+ source, respectively.
Collapse
Affiliation(s)
- Kulbir
- Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati 517507 India
| | - Sandip Das
- Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati 517507 India
| | - Tarali Devi
- Humboldt-Universität zu Berlin, Institut für Chemie Brook-Taylor-Straße 2 D-12489 Berlin Germany
| | - Somnath Ghosh
- Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati 517507 India
| | | | - Pankaj Kumar
- Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati 517507 India
| |
Collapse
|
|
26
|
Valianti VK, Tselios C, Pinakoulaki E. Reversible thermally induced spin crossover in the myoglobin-nitrito adduct directly monitored by resonance Raman spectroscopy. RSC Adv 2023; 13:9020-9025. [PMID: 36950070 PMCID: PMC10025812 DOI: 10.1039/d3ra00225j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 03/12/2023] [Indexed: 03/24/2023] Open
Abstract
Myoglobin has been demonstrated to function as a nitrite reductase to produce nitric oxide during hypoxia. One of the most intriguing aspects of the myoglobin/nitrite interactions revealed so far is the unusual O-binding mode of nitrite to the ferric heme iron, although conflicting data have been reported for the electronic structure of this complex also raising the possibility of linkage isomerism. In this work, we applied resonance Raman spectroscopy in a temperature-dependent approach to investigate the binding of nitrite to ferric myoglobin and the properties of the formed adduct from ambient to low temperatures (293 K to 153 K). At ambient temperature the high spin state of the ferric heme Fe-O-N[double bond, length as m-dash]O species is present and upon decreasing the temperature the low spin state is populated, demonstrating that a thermally-induced spin crossover phenomenon takes place analogous to what has been observed in many transition metal complexes. The observed spin crossover is fully reversible and is not due to linkage isomerism, since the O-binding mode is retained upon the spin transition. The role of the heme pocket environment in controlling the nitrite binding mode and spin transition is discussed.
Collapse
Affiliation(s)
| | - Charalampos Tselios
- Department of Chemistry, University of Cyprus 2109 Aglantzia Cyprus
- Department of Chemical Engineering, Cyprus University of Technology Lemesos Cyprus
| | | |
Collapse
|
|
27
|
Abstract
Resistance arteries and arterioles evolved as specialized blood vessels serving two important functions: (a) regulating peripheral vascular resistance and blood pressure and (b) matching oxygen and nutrient delivery to metabolic demands of organs. These functions require control of vessel lumen cross-sectional area (vascular tone) via coordinated vascular cell responses governed by precise spatial-temporal communication between intracellular signaling pathways. Herein, we provide a contemporary overview of the significant roles that redox switches play in calcium signaling for orchestrated endothelial, smooth muscle, and red blood cell control of arterial vascular tone. Three interrelated themes are the focus: (a) smooth muscle to endothelial communication for vasoconstriction, (b) endothelial to smooth muscle cell cross talk for vasodilation, and (c) oxygen and red blood cell interregulation of vascular tone and blood flow. We intend for this thematic framework to highlight gaps in our current knowledge and potentially spark interest for cross-disciplinary studies moving forward.
Collapse
Affiliation(s)
- Máté Katona
- Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;
| | - Mark T Gladwin
- Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;
- Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Current affiliation: University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Adam C Straub
- Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Center for Microvascular Research, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| |
Collapse
|
|
28
|
DeMartino AW, Poudel L, Dent MR, Chen X, Xu Q, Gladwin BS, Tejero J, Basu S, Alipour E, Jiang Y, Rose JJ, Gladwin MT, Kim-Shapiro DB. Thiol catalyzed formation of NO-ferroheme regulates canonical intravascular NO signaling. RESEARCH SQUARE 2023:rs.3.rs-2402224. [PMID: 36711928 PMCID: PMC9882697 DOI: 10.21203/rs.3.rs-2402224/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Nitric oxide (NO) is an endogenously produced physiological signaling molecule that regulates blood flow and platelet activation. However, both the intracellular and intravascular diffusion of NO is severely limited by scavenging reactions with hemoglobin, myoglobin, and other hemoproteins, raising unanswered questions as to how free NO can signal in hemoprotein-rich environments, like blood and cardiomyocytes. We explored the hypothesis that NO could be stabilized as a ferrous heme-nitrosyl complex (Fe 2+ -NO, NO-ferroheme) either in solution within membranes or bound to albumin. Unexpectedly, we observed a rapid reaction of NO with free ferric heme (Fe 3+ ) and a reduced thiol under physiological conditions to yield NO-ferroheme and a thiyl radical. This thiol-catalyzed reductive nitrosylation reaction occurs readily when the hemin is solubilized in lipophilic environments, such as red blood cell membranes, or bound to serum albumin. NO-ferroheme albumin is stable, even in the presence of excess oxyhemoglobin, and potently inhibits platelet activation. NO-ferroheme-albumin administered intravenously to mice dose-dependently vasodilates at low- to mid-nanomolar concentrations. In conclusion, we report the fastest rate of reductive nitrosylation observed to date to generate a NO-ferroheme molecule that resists oxidative inactivation, is soluble in cell membranes, and is transported intravascularly by albumin to promote potent vasodilation.
Collapse
Affiliation(s)
- Anthony W. DeMartino
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Laxman Poudel
- Department of Physics, Wake Forest University, Winston-Salem, NC 27109, USA
| | - Matthew R. Dent
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Xiukai Chen
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Qinzi Xu
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Brendan S. Gladwin
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jesús Tejero
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
| | - Swati Basu
- Department of Physics, Wake Forest University, Winston-Salem, NC 27109, USA
- Translational Science Center, Wake Forest University, Winston-Salem, NC 27109, USA
| | - Elmira Alipour
- Department of Physics, Wake Forest University, Winston-Salem, NC 27109, USA
| | - Yiyang Jiang
- Department of Physics, Wake Forest University, Winston-Salem, NC 27109, USA
| | - Jason J. Rose
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Mark T. Gladwin
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Daniel B. Kim-Shapiro
- Department of Physics, Wake Forest University, Winston-Salem, NC 27109, USA
- Translational Science Center, Wake Forest University, Winston-Salem, NC 27109, USA
| |
Collapse
|
|
29
|
Zheng Y, Deng W, Liu D, Li Y, Peng K, Lorimer GH, Wang J. Redox and spectroscopic properties of mammalian nitrite reductase-like hemoproteins. J Inorg Biochem 2022; 237:111982. [PMID: 36116154 DOI: 10.1016/j.jinorgbio.2022.111982] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 08/24/2022] [Accepted: 08/25/2022] [Indexed: 01/18/2023]
Abstract
Besides the canonical pathway of L-arginine oxidation to produce nitric oxide (NO) in vivo, the nitrate-nitrite-NO pathway has been widely accepted as another source for circulating NO in mammals, especially under hypoxia. To date, there have been at least ten heme-containing nitrite reductase-like proteins discovered in mammals with activities mainly identified in vitro, including four globins (hemoglobin, myoglobin, neuroglobin (Ngb), cytoglobin (Cygb)), three mitochondrial respiratory chain enzymes (cytochrome c oxidase, cytochrome bc1, cytochrome c), and three other heme proteins (endothelial nitric oxide synthase, cytochrome P450 and indoleamine 2,3-dioxygenase 1 (IDO1)). The pathophysiological functions of these proteins are closely related to their redox and spectroscopic properties, as well as their protein structure, although the physiological roles of Ngb, Cygb and IDO1 remain unclear. So far, comprehensive summaries of the redox and spectroscopic properties of these nitrite reductase-like hemoproteins are still lacking. In this review, we have mainly summarized the published data on the application of ultraviolet-visible, electron paramagnetic resonance, circular dichroism and resonance Raman spectroscopies, and X-ray crystallography in studying nitrite reductase-like activity of these 10 proteins, in order to sort out the relationships among enzymatic function, structure and spectroscopic characterization, which might help in understanding their roles in redox biology and medicine.
Collapse
Affiliation(s)
- Yunlong Zheng
- Hubei University of Technology Autism & Depression Diagnosis and Intervention Institute, Hubei University of Technology, Wuhan, Hubei, China; International Joint Research Center for General Health, Precision Medicine & Nutrition, Hubei University of Technology, Wuhan, Hubei, China; Department of Biomedicine and Biopharmacology, Hubei University of Technology, Wuhan, Hubei, China
| | - Wenwen Deng
- Hubei University of Technology Autism & Depression Diagnosis and Intervention Institute, Hubei University of Technology, Wuhan, Hubei, China; International Joint Research Center for General Health, Precision Medicine & Nutrition, Hubei University of Technology, Wuhan, Hubei, China; Department of Biomedicine and Biopharmacology, Hubei University of Technology, Wuhan, Hubei, China
| | - Di Liu
- Hubei University of Technology Autism & Depression Diagnosis and Intervention Institute, Hubei University of Technology, Wuhan, Hubei, China; International Joint Research Center for General Health, Precision Medicine & Nutrition, Hubei University of Technology, Wuhan, Hubei, China; Department of Biomedicine and Biopharmacology, Hubei University of Technology, Wuhan, Hubei, China
| | - Youheng Li
- Hubei University of Technology Autism & Depression Diagnosis and Intervention Institute, Hubei University of Technology, Wuhan, Hubei, China; International Joint Research Center for General Health, Precision Medicine & Nutrition, Hubei University of Technology, Wuhan, Hubei, China; Department of Biomedicine and Biopharmacology, Hubei University of Technology, Wuhan, Hubei, China
| | - Kang Peng
- Hubei University of Technology Autism & Depression Diagnosis and Intervention Institute, Hubei University of Technology, Wuhan, Hubei, China; International Joint Research Center for General Health, Precision Medicine & Nutrition, Hubei University of Technology, Wuhan, Hubei, China; Department of Biomedicine and Biopharmacology, Hubei University of Technology, Wuhan, Hubei, China
| | | | - Jun Wang
- Hubei University of Technology Autism & Depression Diagnosis and Intervention Institute, Hubei University of Technology, Wuhan, Hubei, China; International Joint Research Center for General Health, Precision Medicine & Nutrition, Hubei University of Technology, Wuhan, Hubei, China; Department of Biomedicine and Biopharmacology, Hubei University of Technology, Wuhan, Hubei, China.
| |
Collapse
|
|
30
|
Jacobs M, Geiger M, Summers S, Janes T, Boyea R, Zinn K, Aburashed R, Spence D. Interferon-β Decreases the Hypermetabolic State of Red Blood Cells from Patients with Multiple Sclerosis. ACS Chem Neurosci 2022; 13:2658-2665. [PMID: 35946788 DOI: 10.1021/acschemneuro.2c00332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Multiple sclerosis (MS) is an inflammatory disease characterized by damage to the myelin sheath surrounding axons in the central nervous system. While the exact mechanism of this destruction is unknown, excess nitric oxide (NO) and adenosine triphosphate (ATP) have been measured in tissues and fluids obtained from people with MS. Here, incubation of interferon-beta (IFN-β), an MS drug with an unknown mechanism of action, with red blood cells (RBCs) obtained from people with MS provide evidence of a potential hypermetabolic state in the MS RBC that is decreased with IFN-β intervention. Specifically, binding of all three components of an albumin/C-peptide/Zn2+ complex to MS RBCs was significantly increased in comparison to control RBCs. For example, the binding of C-peptide to MS RBCs was significantly increased (3.4 ± 0.1 nM) compared to control RBCs (1.6 ± 0.2 nM). However, C-peptide binding to MS RBCs was reduced to a value (1.6 ± 0.3 nM) statistically equal to that of control RBCs in the presence of 2 nM IFN-β. Similar trends were measured for albumin and Zn2+ binding to RBCs when in the presence of IFN-β. RBC function was also affected by incubation of cells with IFN-β. Specifically, RBC-derived ATP and measurable membrane GLUT1 were both significantly decreased (56 and 24%, respectively) in the presence of IFN-β. Collectively, our results suggest that IFN-β inhibits albumin binding to the RBC, thereby reducing its ability to deliver ligands such as C-peptide and Zn2+ to the cell and normalizing the basal hypermetabolic state.
Collapse
Affiliation(s)
- M Jacobs
- Department of Comparative Medicine and Integrative Biology, Michigan State University, East Lansing, Michigan 48824, United States.,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan 48824, United States
| | - M Geiger
- Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States.,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan 48824, United States
| | - S Summers
- Department of Biomedical Engineering, Michigan State University, East Lansing, Michigan 48824, United States.,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan 48824, United States
| | - T Janes
- Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
| | - R Boyea
- Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
| | - K Zinn
- Department of Biomedical Engineering, Michigan State University, East Lansing, Michigan 48824, United States.,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan 48824, United States
| | - R Aburashed
- Memorial Healthcare Institute for Neuroscience, Michigan State University, East Lansing, Michigan 48824, United States
| | - D Spence
- Department of Biomedical Engineering, Michigan State University, East Lansing, Michigan 48824, United States.,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan 48824, United States
| |
Collapse
|
|
31
|
Kaliszuk SJ, Morgan NI, Ayers TN, Sparacino Watkins CE, DeMartino AW, Bocian K, Ragireddy V, Tong Q, Tejero J. Regulation of nitrite reductase and lipid binding properties of cytoglobin by surface and distal histidine mutations. Nitric Oxide 2022; 125-126:12-22. [PMID: 35667547 PMCID: PMC9283305 DOI: 10.1016/j.niox.2022.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/21/2022] [Accepted: 06/01/2022] [Indexed: 12/30/2022]
Abstract
Cytoglobin is a hemoprotein widely expressed in fibroblasts and related cell lineages with yet undefined physiological function. Cytoglobin, as other heme proteins, can reduce nitrite to nitric oxide (NO) providing a route to generate NO in vivo in low oxygen conditions. In addition, cytoglobin can also bind lipids such as oleic acid and cardiolipin with high affinity. These two processes are potentially relevant to cytoglobin function. Little is known about how specific amino acids contribute to nitrite reduction and lipid binding. Here we investigate the role of the distal histidine His81 (E7) and several surface residues on the regulation of nitrite reduction and lipid binding. We observe that the replacement of His81 (E7) greatly increases heme reactivity towards nitrite, with nitrite reduction rate constants of up to 1100 M-1s-1 for the His81Ala mutant. His81 (E7) mutation causes a small decrease in lipid binding affinity, however experiments on the presence of imidazole indicate that His81 (E7) does not compete with the lipid for the binding site. Mutations of the surface residues Arg84 and Lys116 largely impair lipid binding. Our results suggest that dissociation of His81 (E7) from the heme mediates the formation of a hydrophobic cavity in the proximal heme side that can accommodate the lipid, with important contributions of the hydrophobic patch around residues Thr91, Val105, and Leu108, whereas the positive charges from Arg84 and Lys116 stabilize the carboxyl group of the fatty acid. Gain and loss-of-function mutations described here can serve as tools to study in vivo the physiological role of these putative cytoglobin functions.
Collapse
Affiliation(s)
- Stefan J Kaliszuk
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Natasha I Morgan
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Taylor N Ayers
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Courtney E Sparacino Watkins
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Anthony W DeMartino
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Kaitlin Bocian
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Venkata Ragireddy
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Qin Tong
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Jesús Tejero
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, 15260, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
| |
Collapse
|
|
32
|
Giordano D, Verde C, Corti P. Nitric Oxide Production and Regulation in the Teleost Cardiovascular System. Antioxidants (Basel) 2022; 11:957. [PMID: 35624821 PMCID: PMC9137985 DOI: 10.3390/antiox11050957] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/06/2022] [Accepted: 05/09/2022] [Indexed: 01/08/2023] Open
Abstract
Nitric Oxide (NO) is a free radical with numerous critical signaling roles in vertebrate physiology. Similar to mammals, in the teleost system the generation of sufficient amounts of NO is critical for the physiological function of the cardiovascular system. At the same time, NO amounts are strictly controlled and kept within basal levels to protect cells from NO toxicity. Changes in oxygen tension highly influence NO bioavailability and can modulate the mechanisms involved in maintaining the NO balance. While NO production and signaling appears to have general similarities with mammalian systems, the wide range of environmental adaptations made by fish, particularly with regards to differing oxygen availabilities in aquatic habitats, creates a foundation for a variety of in vivo models characterized by different implications of NO production and signaling. In this review, we present the biology of NO in the teleost cardiovascular system and summarize the mechanisms of NO production and signaling with a special emphasis on the role of globin proteins in NO metabolism.
Collapse
Affiliation(s)
- Daniela Giordano
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Via Pietro Castellino 111, 80131 Napoli, Italy; (D.G.); (C.V.)
- Department of Marine Biotechnology, Stazione Zoologica Anton Dohrn (SZN), Villa Comunale, 80121 Napoli, Italy
| | - Cinzia Verde
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Via Pietro Castellino 111, 80131 Napoli, Italy; (D.G.); (C.V.)
- Department of Marine Biotechnology, Stazione Zoologica Anton Dohrn (SZN), Villa Comunale, 80121 Napoli, Italy
| | - Paola Corti
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| |
Collapse
|
|
33
|
Liu T, Schroeder H, Power GG, Blood AB. A physiologically relevant role for NO stored in vascular smooth muscle cells: A novel theory of vascular NO signaling. Redox Biol 2022; 53:102327. [PMID: 35605454 PMCID: PMC9126848 DOI: 10.1016/j.redox.2022.102327] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/16/2022] [Accepted: 04/29/2022] [Indexed: 01/16/2023] Open
Abstract
S-nitrosothiols (SNO), dinitrosyl iron complexes (DNIC), and nitroglycerine (NTG) dilate vessels via activation of soluble guanylyl cyclase (sGC) in vascular smooth muscle cells. Although these compounds are often considered to be nitric oxide (NO) donors, attempts to ascribe their vasodilatory activity to NO-donating properties have failed. Even more puzzling, many of these compounds have vasodilatory potency comparable to or even greater than that of NO itself, despite low membrane permeability. This raises the question: How do these NO adducts activate cytosolic sGC when their NO moiety is still outside the cell? In this review, we classify these compounds as ‘nitrodilators’, defined by their potent NO-mimetic vasoactivities despite not releasing requisite amounts of free NO. We propose that nitrodilators activate sGC via a preformed nitrodilator-activated NO store (NANOS) found within the vascular smooth muscle cell. We reinterpret vascular NO handling in the framework of this NANOS paradigm, and describe the knowledge gaps and perspectives of this novel model.
Collapse
|
|
34
|
Effects of Prolonged Exposure to Hypobaric Hypoxia on Oxidative Stress: Overwintering in Antarctic Concordia Station. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4430032. [PMID: 35535360 PMCID: PMC9078816 DOI: 10.1155/2022/4430032] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/25/2022] [Accepted: 04/09/2022] [Indexed: 12/14/2022]
Abstract
Concordia Station is the permanent, research station on the Antarctic Plateau at 3230 m. During the eleventh winter-over campaign (DC11-2015; February 2015 to November 2015) at Antarctic Concordia Station, 13 healthy team members were studied and blood samples were collected at six different time points: baseline measurements (T0), performed at sea level before the departure, and during the campaign at 3, 7, 20, 90, and 300 days after arrival at Concordia Station. Reducing the partial pressure of O2 as barometric pressure falls, hypobaric hypoxia (HH) triggers several physiological adaptations. Among the others, increased oxidative stress and enhanced generation of reactive oxygen/nitrogen species (ROS/RNS), resulting in severe oxidative damage, were observed, which can share potential physiopathological mechanisms associated with many diseases. This study characterized the extent and time-course changes after acute and chronic HH exposure, elucidating possible fundamental mechanisms of adaptation. ROS, oxidative stress biomarkers, nitric oxide, and proinflammatory cytokines significantly increased (range 24-135%) during acute and chronic hypoxia exposure (peak 20th day) with a decrease in antioxidant capacity (peak 90th day: -52%). Results suggest that the adaptive response of oxidative stress balance to HH requires a relatively long time, more than 300th days, as all the observed variables do not return to the preexposition level. These findings may also be relevant to patients in whom oxygen availability is limited through disease (i.e., chronic heart and lung and/or kidney disease) and/or during long-duration space missions.
Collapse
|
|
35
|
Foley EL, Hvitved AN, Eich RF, Olson JS. Mechanisms of nitric oxide reactions with Globins using mammalian myoglobin as a model system. J Inorg Biochem 2022; 233:111839. [DOI: 10.1016/j.jinorgbio.2022.111839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 04/13/2022] [Accepted: 04/16/2022] [Indexed: 12/15/2022]
|
|
36
|
Keller TCS, Lechauve C, Keller AS, Brooks S, Weiss MJ, Columbus L, Ackerman H, Cortese-Krott MM, Isakson BE. The role of globins in cardiovascular physiology. Physiol Rev 2022; 102:859-892. [PMID: 34486392 PMCID: PMC8799389 DOI: 10.1152/physrev.00037.2020] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 12/11/2022] Open
Abstract
Globin proteins exist in every cell type of the vasculature, from erythrocytes to endothelial cells, vascular smooth muscle cells, and peripheral nerve cells. Many globin subtypes are also expressed in muscle tissues (including cardiac and skeletal muscle), in other organ-specific cell types, and in cells of the central nervous system (CNS). The ability of each of these globins to interact with molecular oxygen (O2) and nitric oxide (NO) is preserved across these contexts. Endothelial α-globin is an example of extraerythrocytic globin expression. Other globins, including myoglobin, cytoglobin, and neuroglobin, are observed in other vascular tissues. Myoglobin is observed primarily in skeletal muscle and smooth muscle cells surrounding the aorta or other large arteries. Cytoglobin is found in vascular smooth muscle but can also be expressed in nonvascular cell types, especially in oxidative stress conditions after ischemic insult. Neuroglobin was first observed in neuronal cells, and its expression appears to be restricted mainly to the CNS and the peripheral nervous system. Brain and CNS neurons expressing neuroglobin are positioned close to many arteries within the brain parenchyma and can control smooth muscle contraction and thus tissue perfusion and vascular reactivity. Overall, reactions between NO and globin heme iron contribute to vascular homeostasis by regulating vasodilatory NO signals and scavenging reactive species in cells of the mammalian vascular system. Here, we discuss how globin proteins affect vascular physiology, with a focus on NO biology, and offer perspectives for future study of these functions.
Collapse
Affiliation(s)
- T C Stevenson Keller
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia
- Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Christophe Lechauve
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Alexander S Keller
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Steven Brooks
- Physiology Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Rockville, Maryland
| | - Mitchell J Weiss
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Linda Columbus
- Department of Chemistry, University of Virginia, Charlottesville, Virginia
| | - Hans Ackerman
- Physiology Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Rockville, Maryland
| | - Miriam M Cortese-Krott
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Brant E Isakson
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia
- Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, Virginia
| |
Collapse
|
|
37
|
Premont RT, Singel DJ, Stamler JS. The enzymatic function of the honorary enzyme: S-nitrosylation of hemoglobin in physiology and medicine. Mol Aspects Med 2022; 84:101056. [PMID: 34852941 PMCID: PMC8821404 DOI: 10.1016/j.mam.2021.101056] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/22/2021] [Accepted: 11/24/2021] [Indexed: 11/16/2022]
Abstract
The allosteric transition within tetrameric hemoglobin (Hb) that allows both full binding to four oxygen molecules in the lung and full release of four oxygens in hypoxic tissues would earn Hb the moniker of 'honorary enzyme'. However, the allosteric model for oxygen binding in hemoglobin overlooked the essential role of blood flow in tissue oxygenation that is essential for life (aka autoregulation of blood flow). That is, blood flow, not oxygen content of blood, is the principal determinant of oxygen delivery under most conditions. With the discovery that hemoglobin carries a third biologic gas, nitric oxide (NO) in the form of S-nitrosothiol (SNO) at β-globin Cys93 (βCys93), and that formation and export of SNO to dilate blood vessels are linked to hemoglobin allostery through enzymatic activity, this title is honorary no more. This chapter reviews evidence that hemoglobin formation and release of SNO is a critical mediator of hypoxic autoregulation of blood flow in tissues leading to oxygen delivery, considers the physiological implications of a 3-gas respiratory cycle (O2/NO/CO2) and the pathophysiological consequences of its dysfunction. Opportunities for therapeutic intervention to optimize oxygen delivery at the level of tissue blood flow are highlighted.
Collapse
Affiliation(s)
- Richard T Premont
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA
| | - David J Singel
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, 59717, USA
| | - Jonathan S Stamler
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA.
| |
Collapse
|
|
38
|
Lehnert N, Kim E, Dong HT, Harland JB, Hunt AP, Manickas EC, Oakley KM, Pham J, Reed GC, Alfaro VS. The Biologically Relevant Coordination Chemistry of Iron and Nitric Oxide: Electronic Structure and Reactivity. Chem Rev 2021; 121:14682-14905. [PMID: 34902255 DOI: 10.1021/acs.chemrev.1c00253] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Nitric oxide (NO) is an important signaling molecule that is involved in a wide range of physiological and pathological events in biology. Metal coordination chemistry, especially with iron, is at the heart of many biological transformations involving NO. A series of heme proteins, nitric oxide synthases (NOS), soluble guanylate cyclase (sGC), and nitrophorins, are responsible for the biosynthesis, sensing, and transport of NO. Alternatively, NO can be generated from nitrite by heme- and copper-containing nitrite reductases (NIRs). The NO-bearing small molecules such as nitrosothiols and dinitrosyl iron complexes (DNICs) can serve as an alternative vehicle for NO storage and transport. Once NO is formed, the rich reaction chemistry of NO leads to a wide variety of biological activities including reduction of NO by heme or non-heme iron-containing NO reductases and protein post-translational modifications by DNICs. Much of our understanding of the reactivity of metal sites in biology with NO and the mechanisms of these transformations has come from the elucidation of the geometric and electronic structures and chemical reactivity of synthetic model systems, in synergy with biochemical and biophysical studies on the relevant proteins themselves. This review focuses on recent advancements from studies on proteins and model complexes that not only have improved our understanding of the biological roles of NO but also have provided foundations for biomedical research and for bio-inspired catalyst design in energy science.
Collapse
Affiliation(s)
- Nicolai Lehnert
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
| | - Eunsuk Kim
- Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States
| | - Hai T Dong
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
| | - Jill B Harland
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
| | - Andrew P Hunt
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
| | - Elizabeth C Manickas
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
| | - Kady M Oakley
- Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States
| | - John Pham
- Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States
| | - Garrett C Reed
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
| | - Victor Sosa Alfaro
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
| |
Collapse
|
|
39
|
Kosmachevskaya OV, Nasybullina EI, Shumaev KB, Novikova NN, Topunov AF. Protective Effect of Dinitrosyl Iron Complexes Bound with Hemoglobin on Oxidative Modification by Peroxynitrite. Int J Mol Sci 2021; 22:13649. [PMID: 34948445 PMCID: PMC8703631 DOI: 10.3390/ijms222413649] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/09/2021] [Accepted: 12/17/2021] [Indexed: 12/21/2022] Open
Abstract
Dinitrosyl iron complexes (DNICs) are a physiological form of nitric oxide (•NO) in an organism. They are able not only to deposit and transport •NO, but are also to act as antioxidant and antiradical agents. However, the mechanics of hemoglobin-bound DNICs (Hb-DNICs) protecting Hb against peroxynitrite-caused, mediated oxidative modification have not yet been scrutinized. Through EPR spectroscopy we show that Hb-DNICs are destroyed under the peroxynitrite action in a dose-dependent manner. At the same time, DNICs inhibit the oxidation of tryptophan and tyrosine residues and formation of carbonyl derivatives. They also prevent the formation of covalent crosslinks between Hb subunits and degradation of a heme group. These effects can arise from the oxoferryl heme form being reduced, and they can be connected with the ability of DNICs to directly intercept peroxynitrite and free radicals, which emerge due to its homolysis. These data show that DNICs may ensure protection from myocardial ischemia.
Collapse
Affiliation(s)
- Olga V. Kosmachevskaya
- Research Center of Biotechnology of the Russian Academy of Sciences, Bach Institute of Biochemistry, 119071 Moscow, Russia; (O.V.K.); (E.I.N.); (K.B.S.)
| | - Elvira I. Nasybullina
- Research Center of Biotechnology of the Russian Academy of Sciences, Bach Institute of Biochemistry, 119071 Moscow, Russia; (O.V.K.); (E.I.N.); (K.B.S.)
| | - Konstantin B. Shumaev
- Research Center of Biotechnology of the Russian Academy of Sciences, Bach Institute of Biochemistry, 119071 Moscow, Russia; (O.V.K.); (E.I.N.); (K.B.S.)
| | | | - Alexey F. Topunov
- Research Center of Biotechnology of the Russian Academy of Sciences, Bach Institute of Biochemistry, 119071 Moscow, Russia; (O.V.K.); (E.I.N.); (K.B.S.)
| |
Collapse
|
|
40
|
Dent MR, DeMartino AW, Tejero J, Gladwin MT. Endogenous Hemoprotein-Dependent Signaling Pathways of Nitric Oxide and Nitrite. Inorg Chem 2021; 60:15918-15940. [PMID: 34313417 PMCID: PMC9167621 DOI: 10.1021/acs.inorgchem.1c01048] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Interdisciplinary research at the interface of chemistry, physiology, and biomedicine have uncovered pivotal roles of nitric oxide (NO) as a signaling molecule that regulates vascular tone, platelet aggregation, and other pathways relevant to human health and disease. Heme is central to physiological NO signaling, serving as the active site for canonical NO biosynthesis in nitric oxide synthase (NOS) enzymes and as the highly selective NO binding site in the soluble guanylyl cyclase receptor. Outside of the primary NOS-dependent biosynthetic pathway, other hemoproteins, including hemoglobin and myoglobin, generate NO via the reduction of nitrite. This auxiliary hemoprotein reaction unlocks a "second axis" of NO signaling in which nitrite serves as a stable NO reservoir. In this Forum Article, we highlight these NO-dependent physiological pathways and examine complex chemical and biochemical reactions that govern NO and nitrite signaling in vivo. We focus on hemoprotein-dependent reaction pathways that generate and consume NO in the presence of nitrite and consider intermediate nitrogen oxides, including NO2, N2O3, and S-nitrosothiols, that may facilitate nitrite-based signaling in blood vessels and tissues. We also discuss emergent therapeutic strategies that leverage our understanding of these key reaction pathways to target NO signaling and treat a wide range of diseases.
Collapse
Affiliation(s)
- Matthew R Dent
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Anthony W DeMartino
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Jesús Tejero
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Mark T Gladwin
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| |
Collapse
|
|
41
|
Akhtar N, Biswas O, Manna D. Stimuli-responsive transmembrane anion transport by AIE-active fluorescent probes. Org Biomol Chem 2021; 19:7446-7459. [PMID: 34612363 DOI: 10.1039/d1ob00584g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Anticancer drug resistance implicates multifunctional mechanisms, and hypoxia is one of the key factors in therapeutic resistance. Hypoxia-specific therapy is considered an extremely effective strategy to fight against cancer. The development of small molecule-based synthetic anion transporters has also recently drawn attention for their potential therapeutic applications against several ion-transport-associated diseases, such as cancer and others. Herein, we describe the development of a hypoxia-responsive proanionophore to trigger controlled transport of anions across membranes under pathogenic conditions. Herein, we report the development of tetraphenylethene (TPE)-based anion transporters. The sulfonium-linked p-nitrobenzyl containing TPE-based proanionophore could be converted into a lipophilic fluorescent Cl- ion carrier in a hypoxic or reductive environment. Stimuli such as nitroreductase (NTR) and glutathione (GSH) mediated regeneration of the TPE-based active Cl- ion transporter also showed aggregation-induced emission (AIE) properties. We hypothesize that such hypoxia and reductive stimuli activatable proanionophores have tremendous potential to fight against channelopathies, including cancer.
Collapse
Affiliation(s)
- Nasim Akhtar
- Department of Chemistry, Indian Institute of Technology Guwahati, Assam 781039, India.
| | | | | |
Collapse
|
|
42
|
Affiliation(s)
- Mark T Gladwin
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, PA
| |
Collapse
|
|
43
|
Massa CM, Liu Z, Taylor S, Pettit AP, Stakheyeva MN, Korotkova E, Popova V, Atochina-Vasserman EN, Gow AJ. Biological Mechanisms of S-Nitrosothiol Formation and Degradation: How Is Specificity of S-Nitrosylation Achieved? Antioxidants (Basel) 2021; 10:antiox10071111. [PMID: 34356344 PMCID: PMC8301044 DOI: 10.3390/antiox10071111] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/03/2021] [Accepted: 06/08/2021] [Indexed: 01/21/2023] Open
Abstract
The modification of protein cysteine residues underlies some of the diverse biological functions of nitric oxide (NO) in physiology and disease. The formation of stable nitrosothiols occurs under biologically relevant conditions and time scales. However, the factors that determine the selective nature of this modification remain poorly understood, making it difficult to predict thiol targets and thus construct informatics networks. In this review, the biological chemistry of NO will be considered within the context of nitrosothiol formation and degradation whilst considering how specificity is achieved in this important post-translational modification. Since nitrosothiol formation requires a formal one-electron oxidation, a classification of reaction mechanisms is proposed regarding which species undergoes electron abstraction: NO, thiol or S-NO radical intermediate. Relevant kinetic, thermodynamic and mechanistic considerations will be examined and the impact of sources of NO and the chemical nature of potential reaction targets is also discussed.
Collapse
Affiliation(s)
- Christopher M. Massa
- Department of Pharmacology & Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08848, USA; (C.M.M.); (Z.L.); (S.T.); (A.P.P.)
| | - Ziping Liu
- Department of Pharmacology & Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08848, USA; (C.M.M.); (Z.L.); (S.T.); (A.P.P.)
| | - Sheryse Taylor
- Department of Pharmacology & Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08848, USA; (C.M.M.); (Z.L.); (S.T.); (A.P.P.)
| | - Ashley P. Pettit
- Department of Pharmacology & Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08848, USA; (C.M.M.); (Z.L.); (S.T.); (A.P.P.)
| | - Marena N. Stakheyeva
- RASA Center in Tomsk, Tomsk Polytechnic University, 634050 Tomsk, Russia; (M.N.S.); (E.N.A.-V.)
- Institute of Natural Resources, Tomsk Polytechnic University, Lenin Av. 30, 634050 Tomsk, Russia; (E.K.); (V.P.)
| | - Elena Korotkova
- Institute of Natural Resources, Tomsk Polytechnic University, Lenin Av. 30, 634050 Tomsk, Russia; (E.K.); (V.P.)
| | - Valentina Popova
- Institute of Natural Resources, Tomsk Polytechnic University, Lenin Av. 30, 634050 Tomsk, Russia; (E.K.); (V.P.)
| | - Elena N. Atochina-Vasserman
- RASA Center in Tomsk, Tomsk Polytechnic University, 634050 Tomsk, Russia; (M.N.S.); (E.N.A.-V.)
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Andrew J. Gow
- Department of Pharmacology & Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08848, USA; (C.M.M.); (Z.L.); (S.T.); (A.P.P.)
- RASA Center in Tomsk, Tomsk Polytechnic University, 634050 Tomsk, Russia; (M.N.S.); (E.N.A.-V.)
- Correspondence: ; Tel.: +1-848-445-4612
| |
Collapse
|
|
44
|
Kosmachevskaya OV, Nasybullina EI, Shumaev KB, Chumikina LV, Arabova LI, Yaglova NV, Obernikhin SS, Topunov AF. Dinitrosyl Iron Complexes with Glutathione Ligands Intercept Peroxynitrite and Protect Hemoglobin from Oxidative Modification. APPL BIOCHEM MICRO+ 2021. [DOI: 10.1134/s0003683821040098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
|
|
45
|
Wang J, Applefeld WN, Sun J, Solomon SB, Feng J, Couse ZG, Risoleo TF, Danner RL, Tejero J, Lertora J, Alipour E, Basu S, Sachdev V, Kim-Shapiro DB, Gladwin MT, Klein HG, Natanson C. Mechanistic insights into cell-free hemoglobin-induced injury during septic shock. Am J Physiol Heart Circ Physiol 2021; 320:H2385-H2400. [PMID: 33989079 DOI: 10.1152/ajpheart.00092.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cell-free hemoglobin (CFH) levels are elevated in septic shock and are higher in nonsurvivors. Whether CFH is only a marker of sepsis severity or is involved in pathogenesis is unknown. This study aimed to investigate whether CFH worsens sepsis-associated injuries and to determine potential mechanisms of harm. Fifty-one, 10-12 kg purpose-bred beagles were randomized to receive Staphylococcus aureus intrapulmonary challenges or saline followed by CFH infusions (oxyhemoglobin >80%) or placebo. Animals received antibiotics and intensive care support for 96 h. CFH significantly increased mean pulmonary arterial pressures and right ventricular afterload in both septic and nonseptic animals, effects that were significantly greater in nonsurvivors. These findings are consistent with CFH-associated nitric oxide (NO) scavenging and were associated with significantly depressed cardiac function, and worsened shock, lactate levels, metabolic acidosis, and multiorgan failure. In septic animals only, CFH administration significantly increased mean alveolar-arterial oxygenation gradients, also to a significantly greater degree in nonsurvivors. CFH-associated iron levels were significantly suppressed in infected animals, suggesting that bacterial iron uptake worsened pneumonia. Notably, cytokine levels were similar in survivors and nonsurvivors and were not predictive of outcome. In the absence and presence of infection, CFH infusions resulted in pulmonary hypertension, cardiogenic shock, and multiorgan failure, likely through NO scavenging. In the presence of infection alone, CFH infusions worsened oxygen exchange and lung injury, presumably by supplying iron that promoted bacterial growth. CFH elevation, a known consequence of clinical septic shock, adversely impacts sepsis outcomes through more than one mechanism, and is a biologically plausible, nonantibiotic, noncytokine target for therapeutic intervention.NEW & NOTEWORTHY Cell-free hemoglobin (CFH) elevations are a known consequence of clinical sepsis. Using a two-by-two factorial design and extensive physiological and biochemical evidence, we found a direct mechanism of injury related to nitric oxide scavenging leading to pulmonary hypertension increasing right heart afterload, depressed cardiac function, worsening circulatory failure, and death, as well as an indirect mechanism related to iron toxicity. These discoveries alter conventional thinking about septic shock pathogenesis and provide novel therapeutic approaches.
Collapse
Affiliation(s)
- Jeffrey Wang
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Willard N Applefeld
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Junfeng Sun
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Steve B Solomon
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Jing Feng
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Zoe G Couse
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Thomas F Risoleo
- Department of Biomedical Engineering, Tufts University, Medford, Massachusetts
| | - Robert L Danner
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Jesús Tejero
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Juan Lertora
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana
| | - Elmira Alipour
- Department of Physics, Wake Forest University, Winston-Salem, North Carolina
| | - Swati Basu
- Department of Physics, Wake Forest University, Winston-Salem, North Carolina
| | - Vandana Sachdev
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | | | - Mark T Gladwin
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Harvey G Klein
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Charles Natanson
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
| |
Collapse
|
|
46
|
Premont RT, Reynolds JD, Zhang R, Stamler JS. Red Blood Cell-Mediated S-Nitrosohemoglobin-Dependent Vasodilation: Lessons Learned from a β-Globin Cys93 Knock-In Mouse. Antioxid Redox Signal 2021; 34:936-961. [PMID: 32597195 PMCID: PMC8035927 DOI: 10.1089/ars.2020.8153] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 06/25/2020] [Indexed: 12/25/2022]
Abstract
Significance: Red blood cell (RBC)-mediated vasodilation plays an important role in oxygen delivery. This occurs through hemoglobin actions, at least in significant part, to convert heme-bound nitric oxide (NO) (in tense [T]/deoxygenated-state hemoglobin) into vasodilator S-nitrosothiol (SNO) (in relaxed [R]/oxygenated-state hemoglobin), convey SNO through the bloodstream, and release it into tissues to increase blood flow. The coupling of hemoglobin R/T state allostery, both to NO conversion into SNO and to SNO release (along with oxygen), under hypoxia supports the model of a three-gas respiratory cycle (O2/NO/CO2). Recent Advances: Oxygenation of tissues is dependent on a single, strictly conserved Cys residue in hemoglobin (βCys93). Hemoglobin couples SNO formation/release at βCys93 to O2 binding/release at hemes ("thermodynamic linkage"). Mice bearing βCys93Ala hemoglobin that is unable to generate SNO-βCys93 establish that SNO-hemoglobin is important for R/T allostery-regulated vasodilation by RBCs that couple blood flow to tissue oxygenation. Critical Issues: The model for RBC-mediated vasodilation originally proposed by Stamler et al. in 1996 has been largely validated: SNO-βCys93 forms in vivo, dilates blood vessels, and is hypoxia-regulated, and RBCs actuate vasodilation proportionate to hypoxia. Numerous compensations in βCys93Ala animals to alleviate tissue hypoxia (discussed herein) are predicted to preserve vasodilatory responses of RBCs but impair linkage to R/T transition in hemoglobin. This is borne out by loss of responsivity of mutant RBCs to oxygen, impaired blood flow responses to hypoxia, and tissue ischemia in βCys93-mutant animals. Future Directions: SNO-hemoglobin mediates hypoxic vasodilation in the respiratory cycle. This fundamental physiology promises new insights in vascular diseases and blood disorders.
Collapse
Affiliation(s)
- Richard T. Premont
- Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - James D. Reynolds
- Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
- Department of Anesthesiology and Perioperative Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Rongli Zhang
- Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Medicine, Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Jonathan S. Stamler
- Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
- Department of Medicine, Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| |
Collapse
|
|
47
|
Mi Z, Liu L, Zhao Y, Guan J. Selective colorimetric and fluorescence detection of nitroreductase enzymes in living cells. Int J Biol Macromol 2020; 164:932-938. [PMID: 32682972 DOI: 10.1016/j.ijbiomac.2020.07.148] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/09/2020] [Accepted: 07/13/2020] [Indexed: 11/19/2022]
Abstract
Rhodamine dyes bearing aromatic nitro group has been synthesized for nitroreductase enzyme chemosensing applications. The probe is showing very selective turn-on fluorescent response towards nitroreductase enzymes and in hypoxic conditions. The sensor displays a remarkable fluorescent enhancement at 557 nm (λex = 500 nm) without the interference of other biologically relevant species under hypoxic conditions in a physiological medium. The nitro group in the sensor is reduced by the nitroreductase enzyme to the amino group, resulting in the hydrolysis of the probe and subsequent release of highly fluorescent rhodamine 6G dye is observed. This rhodamine based fluorescent probe has been utilized for the imaging of nitroreductase enzymes as well as hypoxia in live cells.
Collapse
Affiliation(s)
- Zhi Mi
- College of Life Science, Shanxi Datong University, Shanxi, Datong 037009, China
| | - Lizhen Liu
- College of Chemistry and Engineering, Shanxi Datong University, Shanxi, Datong 037009, China.
| | - Yan Zhao
- School of Mechanical Engineering, Liaoning Shihua University, Fushun 113001, Liaoning, China
| | - Jianjun Guan
- School of Mechanical Engineering, Liaoning Shihua University, Fushun 113001, Liaoning, China.
| |
Collapse
|
|
48
|
Mukosera GT, Liu T, Manaen M, Zhu L, Power G, Schroeder H, Blood AB. Deferoxamine produces nitric oxide under ferricyanide oxidation, blood incubation, and UV-irradiation. Free Radic Biol Med 2020; 160:458-470. [PMID: 32828952 PMCID: PMC11059783 DOI: 10.1016/j.freeradbiomed.2020.08.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 08/03/2020] [Accepted: 08/09/2020] [Indexed: 11/29/2022]
Abstract
Deferoxamine (DFO), an iron chelator, is used therapeutically for the removal of excess iron in multiple clinical conditions such as beta thalassemia and intracerebral hemorrhage. DFO is also used as an iron chelator and hypoxia-mimetic agent in in vivo and in vitro basic research. Here we unexpectedly discover DFO to be a nitric oxide (NO) precursor in experiments where it was intended to act as an iron chelator. Production of NO from aqueous solutions of DFO was directly observed by ozone-based chemiluminescence using a ferricyanide-based assay and was confirmed by electron paramagnetic resonance (EPR). DFO also produced NO following exposure to ultraviolet light, and its incubation with sheep adult and fetal blood resulted in considerable formation of iron nitrosyl hemoglobin, as confirmed by both visible spectroscopy and EPR. These results suggest that experiments using DFO can be confounded by concomitant production of NO, and offer new insight into some of DFO's unexplained clinical side effects such as hypotension.
Collapse
Affiliation(s)
- George T Mukosera
- Lawrence D Longo Center for Perinatal Biology and Department of Pediatrics, Loma Linda University, 11175 Campus Street, Loma Linda, CA, 92354, USA
| | - Taiming Liu
- Lawrence D Longo Center for Perinatal Biology and Department of Pediatrics, Loma Linda University, 11175 Campus Street, Loma Linda, CA, 92354, USA
| | - Meshach Manaen
- Lawrence D Longo Center for Perinatal Biology and Department of Pediatrics, Loma Linda University, 11175 Campus Street, Loma Linda, CA, 92354, USA
| | - Lingchao Zhu
- Department of Chemistry, University of California-Riverside 501 Big Springs Road, Riverside, CA 92521, USA
| | - Gordon Power
- Lawrence D Longo Center for Perinatal Biology and Department of Pediatrics, Loma Linda University, 11175 Campus Street, Loma Linda, CA, 92354, USA
| | - Hobe Schroeder
- Lawrence D Longo Center for Perinatal Biology and Department of Pediatrics, Loma Linda University, 11175 Campus Street, Loma Linda, CA, 92354, USA
| | - Arlin B Blood
- Lawrence D Longo Center for Perinatal Biology and Department of Pediatrics, Loma Linda University, 11175 Campus Street, Loma Linda, CA, 92354, USA.
| |
Collapse
|
|
49
|
Boddu RS, Perumal O, K D. Microbial nitroreductases: A versatile tool for biomedical and environmental applications. Biotechnol Appl Biochem 2020; 68:1518-1530. [PMID: 33156534 DOI: 10.1002/bab.2073] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 11/02/2020] [Indexed: 12/24/2022]
Abstract
Nitroreductases, enzymes found mostly in bacteria and also in few eukaryotes, use nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor for their activity and metabolize an enormous list of a diverse nitro group-containing compounds. Nitroreductases that are capable of metabolizing nitroaromatic and nitro heterocyclic compounds have drawn great attention in recent years owing to their biotechnological, biomedical, environmental, and human impact. These enzymes attracted medicinal chemists and pharmacologists because of their prodrug selectivity for activation/reduction of nitro compounds that wipe out pathogens/cancer cells, leaving the host/normal cells unharmed. It is applied in diverse fields of study like prodrug activation in treating cancer and leishmaniasis, designing fluorescent probes for hypoxia detection, cell imaging, ablation of specific cell types, biodegradation of nitro-pollutants, and interpretation of mutagenicity of nitro compounds. Keeping in view the immense prospects of these enzymes and a large number of research contributions in this area, the present review encompasses the enzymatic reaction mechanism, their role in antibiotic resistance, hypoxia sensing, cell imaging, cancer therapy, reduction of recalcitrant nitro chemicals, enzyme variants, and their specificity to substrates, reaction products, and their applications.
Collapse
Affiliation(s)
- Ramya Sree Boddu
- Department of Biotechnology, National Institute of Technology, Warangal, India
| | - Onkara Perumal
- Department of Biotechnology, National Institute of Technology, Warangal, India
| | - Divakar K
- Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur, India
| |
Collapse
|
|
50
|
Amdahl MB, DeMartino AW, Gladwin MT. Inorganic nitrite bioactivation and role in physiological signaling and therapeutics. Biol Chem 2020; 401:201-211. [PMID: 31747370 DOI: 10.1515/hsz-2019-0349] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 11/02/2019] [Indexed: 01/23/2023]
Abstract
The bioactivation of inorganic nitrite refers to the conversion of otherwise 'inert' nitrite to the diatomic signaling molecule nitric oxide (NO), which plays important roles in human physiology and disease, notably in the regulation of vascular tone and blood flow. While the most well-known sources of NO are the nitric oxide synthase (NOS) enzymes, another source of NO is the nitrate-nitrite-NO pathway, whereby nitrite (obtained from reduction of dietary nitrate) is further reduced to form NO. The past few decades have seen extensive study of the mechanisms of NO generation through nitrate and nitrite bioactivation, as well as growing appreciation of the contribution of this pathway to NO signaling in vivo. This review, prepared for the volume 400 celebration issue of Biological Chemistry, summarizes some of the key reactions of the nitrate-nitrite-NO pathway such as reduction, disproportionation, dehydration, and oxidative denitrosylation, as well as current evidence for the contribution of the pathway to human cardiovascular physiology. Finally, ongoing efforts to develop novel medical therapies for multifarious conditions, especially those related to pathologic vasoconstriction and ischemia/reperfusion injury, are also explored.
Collapse
Affiliation(s)
- Matthew B Amdahl
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Anthony W DeMartino
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Mark T Gladwin
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.,Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| |
Collapse
|