|
1
|
Hossain K, Basak A, Majumdar A. Thiocarboxylate and Acid Chloride Mediated Generation of Nitric Oxide from a Dinickel(II)-Bis(ONO) Complex Involving the Formation of Perthionitrite and O-Nitrosyl Carboxylate. J Am Chem Soc 2025; 147:15408-15428. [PMID: 40264297 DOI: 10.1021/jacs.5c01529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
A detailed study for the generation of nitric oxide (NO) upon reaction of a binuclear Ni(II)-bis(ONO) complex with carboxylic acids (RCOOH, R = Me, Ph), thiols (RSH, R = Ph, p-F-C6H4), benzeneselenol (PhSeH), thiocarboxylates (RC(O)S-, R = Me, Ph), thiocarboxylic acids (RC(O)SH, R = Me, Ph), and acid chlorides (RC(O)Cl, R = Me, Ph) has been presented. The reactions of the binuclear Ni(II)-bis(ONO) complex with thiols/selenols give access to unusual dinickel(II)-nitrito-thiolato/selenolato complexes, while the reactions with RC(O)S-, RC(O)SH, and RC(O)Cl offer new mechanistic insights into the generation of perthionitrite (SSNO-) and O-nitrosyl carboxylates (RC(O)ONO), the well-known NO-carrying species in biology. Interestingly, while the reaction of the binuclear Ni(II)-bis(ONO) complex with RC(O)S- involved nucleophilic attack of the latter to the coordinated NO2- to generate SSNO-, the reaction with RC(O)Cl proceeds via the hitherto unknown nucleophilic attack of the coordinated NO2- to the carbonyl carbon of RC(O)Cl to generate RC(O)ONO, which, in turn, produces NO. The present comparative study thus demonstrates new reactions of metal-coordinated NO2- and detailed mechanistic investigations supported by molecular structure determinations and spectroscopic studies and establishes the hitherto unknown reaction of coordinated nitrite with RC(O)Cl to be a highly efficient method for the generation of NO in excellent yield.
Collapse
Affiliation(s)
- Kamal Hossain
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Arindam Basak
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Amit Majumdar
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| |
Collapse
|
|
2
|
Stec NE, Barker FG, Brastianos PK. Targeted treatment for craniopharyngioma. J Neurooncol 2025; 172:503-513. [PMID: 39951179 DOI: 10.1007/s11060-025-04942-0] [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: 10/22/2024] [Accepted: 01/13/2025] [Indexed: 04/04/2025]
Abstract
INTRODUCTION Craniopharyngioma is a rare solid-cystic tumor of the hypothalamopituitary region. Two distinct craniopharyngioma types (formerly subtypes), adamantinomatous and papillary, have been described. These tumors often manifest with neuroendocrine dysfunction, vision problems, hydrocephalus, and cognitive changes. Despite efforts to spare vital brain structures, conventional treatments such as surgery and radiation can exacerbate preceding deficits and contribute to permanent neurologic impairment. Recent studies have identified BRAF-V600E mutations in nearly all papillary craniopharyngiomas (PCP), and CTNNB1/Wnt pathway alterations in adamantinomatous craniopharyngiomas (ACP). These discoveries have advanced our understanding of craniopharyngioma pathogenesis and have opened opportunities for targeted biological treatments. PURPOSE The primary objective of this article is to review the current landscape of targeted treatments in papillary and adamantinomatous craniopharyngioma. RESULTS Treatment of PCP with BRAF/MEK inhibition has demonstrated durable tumor response in the adjuvant and neoadjuvant settings in multiple case studies and one phase II clinical trial. Although treatment advances are more limited for ACP, CTNNB1/Wnt pathway inhibitors showed promising results in pre-clinical studies and are under continued investigation. CONCLUSION The efficacy of BRAF/MEK inhibition in PCP supports the use of targeted therapy in patients with newly diagnosed PCP. The optimal targeted treatment combinations and their timing, duration, long-term effects, and sequencing with traditional therapeutic modalities have not been established and warrant further study. Targeted therapies represent a significant advancement in the field of oncology, and craniopharyngiomas are viable candidates for these approaches pending further research.
Collapse
Affiliation(s)
- Natalie E Stec
- Divisions of Neuro-Oncology and Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA
| | - Fred G Barker
- Department of Neurosurgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA
| | - Priscilla K Brastianos
- Divisions of Neuro-Oncology and Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
| |
Collapse
|
|
3
|
Piknova B, Park JW, Schechter AN. Nitrate as Warden of Nitric Oxide Homeostasis in Mammals. Nutrients 2025; 17:1544. [PMID: 40362853 PMCID: PMC12073257 DOI: 10.3390/nu17091544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2025] [Revised: 04/28/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
Homeostasis is the self-regulating processes in cells and organisms designed to maintain stability of the internal environment while adjusting to external changes. To achieve this dynamic stability, internal conditions oscillate within tightly regulated physiological tolerance limits. In mammals, maintaining nitric oxide (NO) availability appears crucial to sustain relatively constant blood flow into all organs and tissues. We hypothesize that NO homeostasis is one of the most important vital processes for warm-blooded animals. It is impossible to conserve the stability of most other vital substances, such as O2, CO2, blood sugar, pH, and temperature, to name just few, without well-functioning tissue perfusion. NO in mammals is generated either from L-arginine by nitric oxide synthases (NOSs) or by the reduction of nitrate (NO3-) to nitrite (NO2-) and NO by several proteins. Here we first discuss the organization of these two NO metabolic pathways, emphasizing that both pathways "cross" and "funnel" unused NO into the overall nitrate-nitrite-NO pathway. This pathway is cyclic, which gives nitrate a unique place in metabolism and predisposes it as a reservoir for NO. Then, we discuss the role of NO homeostasis that, by maintaining organ and tissue perfusion, supports and preserves constancy of other blood-delivered substances. This "governing" role of NO makes even clearer that the existence of NO storage and precursor molecules is necessary, to avoid NO shortages in cases of the precursor's or storage molecule's temporary unavailability, to ensure uninterrupted tissue access to NO. We propose that the skeletomuscular system and skin act as nitrate reservoirs assuring NO bioavailability at various external and internal conditions.
Collapse
Affiliation(s)
- Barbora Piknova
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20852, USA
| | | | | |
Collapse
|
|
4
|
Atta S, Mandal A, Patra S, Majumdar A. Functional Nonheme Diiron(II) Complexes Catalyze the Direct Reduction of Nitrite to Nitric Oxide in Relevance to the Diiron Protein YtfE. Inorg Chem 2025; 64:7726-7745. [PMID: 40180608 DOI: 10.1021/acs.inorgchem.5c00753] [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: 04/05/2025]
Abstract
The present work reports the functional modeling chemistry of YtfE, which features a nonheme diiron active site and mediates the direct reduction of NO2- to NO. The model complex, [Fe2(HPTP)Cl2]1+ (1), reduces NO2- to NO in a 100% yield within 12 h and generates [Fe4(HPTP)2(μ-O)3(μ-OH)]3+ (2). Similar to YtfE, the reaction involves stepwise oxidation of two Fe(II) centers and product (NO) inhibition, of which the latter produces [Fe2(HPTP)(NO)2Cl2]1+ (3). Complex 3 could also be synthesized by the reaction of [Fe2(HPTP)(NO)2(ClO4)]2+ (4) and chloride. Complex 1 catalyzes the reduction of NO2- to NO in the presence of PhS-, albeit with a low TON of 5, due to the formation of an insoluble product, [Fe2(HPTP)(μ-SPh)Cl2] (5). Another model complex [Fe2(HPTP)(OPr)]1+ (6), reduced NO2- to NO in an 80% yield after 24 h, generated [Fe2(HPTP)(OPr)(NO)2]1+ (7), and offered a TON of 19. The third model complex, [Fe2(HPTP)(ClO4)2]1+ (8), could reduce NO2- to NO in a 100% yield but only after 48 h. A comparison of these results establishes that easy oxidation of the Fe(II) centers, easy accessibility of the Fe(II) centers for the coordination of NO2-, and easy release of NO from the in situ generated dinitrosyl diiron complex increase the efficiency of the functional model complexes of YtfE.
Collapse
Affiliation(s)
- Sayan Atta
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Kolkata 700032, West Bengal, India
| | - Amit Mandal
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Kolkata 700032, West Bengal, India
| | - Suman Patra
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Kolkata 700032, West Bengal, India
| | - Amit Majumdar
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Kolkata 700032, West Bengal, India
| |
Collapse
|
|
5
|
Gonzalez M, Clayton S, Wauson E, Christian D, Tran QK. Promotion of nitric oxide production: mechanisms, strategies, and possibilities. Front Physiol 2025; 16:1545044. [PMID: 39917079 PMCID: PMC11799299 DOI: 10.3389/fphys.2025.1545044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 01/07/2025] [Indexed: 02/09/2025] Open
Abstract
The discovery of nitric oxide (NO) and the role of endothelial cells (ECs) in its production has revolutionized medicine. NO can be produced by isoforms of NO synthases (NOS), including the neuronal (nNOS), inducible (iNOS), and endothelial isoforms (eNOS), and via the non-classical nitrate-nitrite-NO pathway. In particular, endothelium-derived NO, produced by eNOS, is essential for cardiovascular health. Endothelium-derived NO activates soluble guanylate cyclase (sGC) in vascular smooth muscle cells (VSMCs), elevating cyclic GMP (cGMP), causing vasodilation. Over the past four decades, the importance of this pathway in cardiovascular health has fueled the search for strategies to enhance NO bioavailability and/or preserve the outcomes of NO's actions. Currently approved approaches operate in three directions: 1) providing exogenous NO, 2) promoting sGC activity, and 3) preventing degradation of cGMP by inhibiting phosphodiesterase 5 activity. Despite clear benefits, these approaches face challenges such as the development of nitrate tolerance and endothelial dysfunction. This highlights the need for sustainable options that promote endogenous NO production. This review will focus on strategies to promote endogenous NO production. A detailed review of the mechanisms regulating eNOS activity will be first provided, followed by a review of strategies to promote endogenous NO production based on the levels of available preclinical and clinical evidence, and perspectives on future possibilities.
Collapse
Affiliation(s)
| | | | | | | | - Quang-Kim Tran
- Department of Physiology and Pharmacology, Des Moines University Medicine and Health Sciences, West Des Moines, IA, United States
| |
Collapse
|
|
6
|
Karmakar S, Patra S, Halder R, Karmakar S, Majumdar A. Reduction of Nitrite in an Iron(II)-Nitrito Compound by Thiols and Selenol Produces Dinitrosyl Iron Complexes via an {FeNO} 7 Intermediate. Inorg Chem 2024; 63:23202-23220. [PMID: 39569438 DOI: 10.1021/acs.inorgchem.4c03555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2024]
Abstract
Reaction of an Fe(II) complex, [Fe(6-COO--tpa)]1+ (1), with PhE- and NO2- produced [Fe(6-COO--tpa)(EPh)] (E = S, 2a; Se, 3) and [Fe(6-COO--tpa)(κ2-O,O'-NO2)] (4), respectively (6-COOH-tpa is bis(2-pyridylmethyl)(6-carboxyl-2-pyridylmethyl)amine). Treatment of 4 with 2 equiv of PhEH (E = S, Se) produced NO in ∼40% yields, respectively, along with 1 and the DNICs, [Fe(EPh)2(NO)2]1- (E = S, Se). Treatment of 4 with excess PhEH produced NO in similar yields, while 4 was converted to the same DNICs and 2a/3 (instead of 1). The DNICs have been proposed to be generated via the reaction of PhE- with an in situ generated, unstable {FeNO}7 intermediate, [Fe(6-COO--tpa)(NO)]1+ (6), which has also been synthesized separately. Compound 6 reacts with PhS- to generate [Fe(SPh)2(NO)2]1-, thus supporting the proposed reaction pathway. Finally, while the treatment of two unique compounds, featuring inbuilt proton sources, [Fe(6-COO--tpa)(S-C6H4-p-COOH)] (7) and [Fe(6-COO--tpa)(S-C6H4-o-OH)] (8), with 0.5 and 1 equiv of NO2- could produce NO only in 8-26% yields, treatment of 4 with HS-C6H4-p-COOH and HS-C6H4-o-OH produced NO in much higher yields (65-77%). The combined results delineated the importance of coordination of NO2- for the proton-assisted reduction of NO2- to generate NO.
Collapse
Affiliation(s)
- Soumik Karmakar
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Suman Patra
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Ritapravo Halder
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Suchismita Karmakar
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Amit Majumdar
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| |
Collapse
|
|
7
|
Johnson AR, Rao K, Zhang BB, Mullet S, Goetzman E, Gelhaus S, Tejero J, Shiva S. Myoglobin inhibits breast cancer cell fatty acid oxidation and migration via heme-dependent oxidant production and not fatty acid binding. Free Radic Biol Med 2024; 225:208-220. [PMID: 39368517 DOI: 10.1016/j.freeradbiomed.2024.10.258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/17/2024] [Accepted: 10/02/2024] [Indexed: 10/07/2024]
Abstract
The monomeric heme protein myoglobin (Mb) is aberrantly expressed in approximately 40 % of breast tumors. Mb expression is associated with better patient prognosis, yet the molecular mechanisms underlying this effect are unclear. In muscle, Mb's heme moiety confers oxygen storage and delivery. However, prior studies demonstrate that low levels of Mb in cancer cells preclude this function. Several studies propose a fatty acid binding function for Mb via lysine residue K46. Because cancer cells can upregulate fatty acid oxidation (FAO) to fuel cell migration, we tested whether Mb-mediated fatty acid binding modulates FAO and migration. We demonstrate that stable expression of human Mb in MDA-MB-231 breast cancer cells decreases cell migration and FAO. Site-directed mutagenesis of Mb K46 disrupted fatty acid binding but did not improve FAO or migration. Conversely, cells expressing Apo-Mb (with disrupted heme binding) did not show impaired FAO or migration rates, suggesting Mb attenuates FAO and migration via a heme-dependent mechanism rather than through fatty acid binding. Mb's heme-dependent oxidant generation dysregulates migratory gene expression, which is reversed by catalase treatment. Collectively, these data demonstrate that Mb's heme-dependent oxidant production decreases breast cancer cell migration, prompting therapeutic strategies to modulate oxidant production and Mb in tumors.
Collapse
Affiliation(s)
- Aaron R Johnson
- Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Krithika Rao
- Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Bob B Zhang
- Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Steven Mullet
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Eric Goetzman
- Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Stacy Gelhaus
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Jesus Tejero
- Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Sruti Shiva
- Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
| |
Collapse
|
|
8
|
Abbineni PS, Baid S, Weiss MJ. A moonlighting job for α-globin in blood vessels. Blood 2024; 144:834-844. [PMID: 38848504 PMCID: PMC11830976 DOI: 10.1182/blood.2023022192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/08/2024] [Accepted: 05/28/2024] [Indexed: 06/09/2024] Open
Abstract
ABSTRACT Red blood cells express high levels of hemoglobin A tetramer (α2β2) to facilitate oxygen transport. Hemoglobin subunits and related proteins are also expressed at lower levels in other tissues across the animal kingdom. Physiological functions for most nonerythroid globins likely derive from their ability to catalyze reduction-oxidation (redox) reactions via electron transfer through heme-associated iron. An interesting example is illustrated by the recent discovery that α-globin without β-globin is expressed in some arteriolar endothelial cells (ECs). α-globin binds EC nitric oxide (NO) synthase (eNOS) and degrades its enzymatic product NO, a potent vasodilator. Thus, depletion of α-globin in ECs or inhibition of its association with eNOS causes arteriolar relaxation and lowering of blood pressure in mice. Some of these findings have been replicated in isolated human blood vessels, and genetic studies are tractable in populations in which α-thalassemia alleles are prevalent. Two small studies identified associations between loss of α-globin genes in humans and NO-regulated vascular responses elicited by local hypoxia-induced blood flow or thermal stimulation. In a few larger population-based studies, no associations were detected between loss of α-globin genes and blood pressure, ischemic stroke, or pulmonary hypertension. In contrast, a significant positive association between α-globin gene copy number and kidney disease was detected in an African American cohort. Further studies are required to define comprehensively the expression of α-globin in different vascular beds and ascertain their overall impact on normal and pathological vascular physiology.
Collapse
Affiliation(s)
- Prabhodh S. Abbineni
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL
| | - Srishti Baid
- Life Sciences Institute, University of Michigan, Ann Arbor, MI
| | - Mitchell J. Weiss
- Department of Hematology, St Jude Children’s Research Hospital, Memphis, TN
| |
Collapse
|
|
9
|
Yuschen X, Choi JH, Seo J, Sun Y, Lee E, Kim SW, Park HY. Effects of Acute Beetroot Juice Supplementation and Exercise on Cardiovascular Function in Healthy Men in Preliminary Study: A Randomized, Double-Blinded, Placebo-Controlled, and Crossover Trial. Healthcare (Basel) 2024; 12:1240. [PMID: 38998775 PMCID: PMC11241253 DOI: 10.3390/healthcare12131240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 07/14/2024] Open
Abstract
Nitrate-rich beetroot juice (NRBRJ) can potentially enhance exercise performance and improve cardiovascular function, leading to an increased use of NRBRJ over the years. However, the combined effects of NRBRJ supplementation and exercise on cardiovascular function remain unclear. Therefore, this study compared cardiovascular function responses to submaximal exercise with either placebo (PLA) or NRBRJ supplementation in healthy men. Twelve healthy men (aged 25.2 ± 2.3 years) completed the 30-min submaximal cycle ergometer exercise trials corresponding to 70% maximal heart rate (HRmax) with either PLA or NRBRJ supplementation in a random order. The mean exercise load, heart rate (HR), stroke volume (SV), cardiac output (CO), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and total peripheral resistance (TPR) were measured during exercise. The brachial-ankle pulse wave velocity (baPWV) and flow-mediated dilation (FMD) were measured before and after exercise. NRBRJ supplementation was more effective than PLA in increasing the mean exercise load and decreasing DBP and MAP during submaximal exercise. Furthermore, baPWV decreased in the NRBRJ trial and was considerably lower after exercise in the NRBRJ-supplemented group than in the PLA-supplemented group. FMD significantly increased in the PLA and NRBRJ trials; however, NRBRJ supplementation demonstrated a significantly higher FMD before and after exercise than PLA supplementation. In conclusion, acute NRBRJ supplementation and exercise were more effective than PLA supplementation and exercise in improving aerobic exercise capacity and cardiovascular function in healthy men.
Collapse
Affiliation(s)
- Xie Yuschen
- Department of Sports Medicine and Science, Graduate School, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Jae-Ho Choi
- Department of Sports Medicine and Science, Graduate School, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Jisoo Seo
- Department of Sports Medicine and Science, Graduate School, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Yerin Sun
- Department of Sports Medicine and Science, Graduate School, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Eunjoo Lee
- Department of Sports Medicine and Science, Graduate School, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Sung-Woo Kim
- Department of Sports Medicine and Science, Graduate School, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
- Physical Activity and Performance Institute, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Hun-Young Park
- Department of Sports Medicine and Science, Graduate School, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
- Physical Activity and Performance Institute, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| |
Collapse
|
|
10
|
Silva-Cunha M, Lacchini R, Tanus-Santos JE. Facilitating Nitrite-Derived S-Nitrosothiol Formation in the Upper Gastrointestinal Tract in the Therapy of Cardiovascular Diseases. Antioxidants (Basel) 2024; 13:691. [PMID: 38929130 PMCID: PMC11200996 DOI: 10.3390/antiox13060691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 05/30/2024] [Accepted: 05/31/2024] [Indexed: 06/28/2024] Open
Abstract
Cardiovascular diseases (CVDs) are often associated with impaired nitric oxide (NO) bioavailability, a critical pathophysiological alteration in CVDs and an important target for therapeutic interventions. Recent studies have revealed the potential of inorganic nitrite and nitrate as sources of NO, offering promising alternatives for managing various cardiovascular conditions. It is now becoming clear that taking advantage of enzymatic pathways involved in nitrite reduction to NO is very relevant in new therapeutics. However, recent studies have shown that nitrite may be bioactivated in the acidic gastric environment, where nitrite generates NO and a variety of S-nitrosating compounds that result in increased circulating S-nitrosothiol concentrations and S-nitrosation of tissue pharmacological targets. Moreover, transnitrosation reactions may further nitrosate other targets, resulting in improved cardiovascular function in patients with CVDs. In this review, we comprehensively address the mechanisms and relevant effects of nitrate and nitrite-stimulated gastric S-nitrosothiol formation that may promote S-nitrosation of pharmacological targets in various CVDs. Recently identified interfering factors that may inhibit these mechanisms and prevent the beneficial responses to nitrate and nitrite therapy were also taken into consideration.
Collapse
Affiliation(s)
- Mila Silva-Cunha
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil;
| | - Riccardo Lacchini
- Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto 14040-902, Brazil;
| | - Jose E. Tanus-Santos
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil;
| |
Collapse
|
|
11
|
Coutinho LL, Femino EL, Gonzalez AL, Moffat RL, Heinz WF, Cheng RYS, Lockett SJ, Rangel MC, Ridnour LA, Wink DA. NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer. Int J Mol Sci 2024; 25:6103. [PMID: 38892290 PMCID: PMC11173351 DOI: 10.3390/ijms25116103] [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: 02/28/2024] [Revised: 05/24/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
Nitric oxide (NO) and reactive nitrogen species (RNS) exert profound biological impacts dictated by their chemistry. Understanding their spatial distribution is essential for deciphering their roles in diverse biological processes. This review establishes a framework for the chemical biology of NO and RNS, exploring their dynamic reactions within the context of cancer. Concentration-dependent signaling reveals distinctive processes in cancer, with three levels of NO influencing oncogenic properties. In this context, NO plays a crucial role in cancer cell proliferation, metastasis, chemotherapy resistance, and immune suppression. Increased NOS2 expression correlates with poor survival across different tumors, including breast cancer. Additionally, NOS2 can crosstalk with the proinflammatory enzyme cyclooxygenase-2 (COX-2) to promote cancer progression. NOS2 and COX-2 co-expression establishes a positive feed-forward loop, driving immunosuppression and metastasis in estrogen receptor-negative (ER-) breast cancer. Spatial evaluation of NOS2 and COX-2 reveals orthogonal expression, suggesting the unique roles of these niches in the tumor microenvironment (TME). NOS2 and COX2 niche formation requires IFN-γ and cytokine-releasing cells. These niches contribute to poor clinical outcomes, emphasizing their role in cancer progression. Strategies to target these markers include direct inhibition, involving pan-inhibitors and selective inhibitors, as well as indirect approaches targeting their induction or downstream effectors. Compounds from cruciferous vegetables are potential candidates for NOS2 and COX-2 inhibition offering therapeutic applications. Thus, understanding the chemical biology of NO and RNS, their spatial distribution, and their implications in cancer progression provides valuable insights for developing targeted therapies and preventive strategies.
Collapse
Affiliation(s)
- Leandro L. Coutinho
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (L.L.C.); (E.L.F.); (A.L.G.); (R.Y.S.C.)
- Center for Translational Research in Oncology, ICESP/HC, Faculdade de Medicina da Universidade de São Paulo and Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo 01246-000, SP, Brazil;
| | - Elise L. Femino
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (L.L.C.); (E.L.F.); (A.L.G.); (R.Y.S.C.)
| | - Ana L. Gonzalez
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (L.L.C.); (E.L.F.); (A.L.G.); (R.Y.S.C.)
| | - Rebecca L. Moffat
- Optical Microscopy and Analysis Laboratory, Office of Science and Technology Resources, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA;
| | - William F. Heinz
- Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; (W.F.H.); (S.J.L.)
| | - Robert Y. S. Cheng
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (L.L.C.); (E.L.F.); (A.L.G.); (R.Y.S.C.)
| | - Stephen J. Lockett
- Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; (W.F.H.); (S.J.L.)
| | - M. Cristina Rangel
- Center for Translational Research in Oncology, ICESP/HC, Faculdade de Medicina da Universidade de São Paulo and Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo 01246-000, SP, Brazil;
| | - Lisa A. Ridnour
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (L.L.C.); (E.L.F.); (A.L.G.); (R.Y.S.C.)
| | - David A. Wink
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (L.L.C.); (E.L.F.); (A.L.G.); (R.Y.S.C.)
| |
Collapse
|
|
12
|
Johnson AR, Rao K, Zhang BB, Mullet S, Goetzman E, Gelhaus S, Tejero J, Shiva U. Myoglobin Inhibits Breast Cancer Cell Fatty Acid Oxidation and Migration via Heme-dependent Oxidant Production and Not Fatty Acid Binding. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.30.591659. [PMID: 38746370 PMCID: PMC11092581 DOI: 10.1101/2024.04.30.591659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
The monomeric heme protein myoglobin (Mb), traditionally thought to be expressed exclusively in cardiac and skeletal muscle, is now known to be expressed in approximately 40% of breast tumors. While Mb expression is associated with better patient prognosis, the molecular mechanisms by which Mb limits cancer progression are unclear. In muscle, Mb's predominant function is oxygen storage and delivery, which is dependent on the protein's heme moiety. However, prior studies demonstrate that the low levels of Mb expressed in cancer cells preclude this function. Recent studies propose a novel fatty acid binding function for Mb via a lysine residue (K46) in the heme pocket. Given that cancer cells can upregulate fatty acid oxidation (FAO) to maintain energy production for cytoskeletal remodeling during cell migration, we tested whether Mb-mediated fatty acid binding modulates FAO to decrease breast cancer cell migration. We demonstrate that the stable expression of human Mb in MDA-MB-231 breast cancer cells decreases cell migration and FAO. Site-directed mutagenesis of Mb to disrupt Mb fatty acid binding did not reverse Mb-mediated attenuation of FAO or cell migration in these cells. In contrast, cells expressing Apo-Mb, in which heme incorporation was disrupted, showed a reversal of Mb-mediated attenuation of FAO and cell migration, suggesting that Mb attenuates FAO and migration via a heme-dependent mechanism rather than through fatty acid binding. To this end, we show that Mb's heme-dependent oxidant generation propagates dysregulated gene expression of migratory genes, and this is reversed by catalase treatment. Collectively, these data demonstrate that Mb decreases breast cancer cell migration, and this effect is due to heme-mediated oxidant production rather than fatty acid binding. The implication of these results will be discussed in the context of therapeutic strategies to modulate oxidant production and Mb in tumors. Highlights Myoglobin (Mb) expression in MDA-MB-231 breast cancer cells slows migration.Mb expression decreases mitochondrial respiration and fatty acid oxidation.Mb-dependent fatty acid binding does not regulate cell migration or respiration.Mb-dependent oxidant generation decreases mitochondrial metabolism and migration.Mb-derived oxidants dysregulate migratory gene expression.
Collapse
|
|
13
|
Zoladz JA, Grandys M, Smeda M, Kij A, Kurpinska A, Kwiatkowski G, Karasinski J, Hendgen-Cotta U, Chlopicki S, Majerczak J. Myoglobin deficiency impairs maximal oxygen uptake and exercise performance: a lesson from Mb -/- mice. J Physiol 2024; 602:855-873. [PMID: 38376957 DOI: 10.1113/jp285067] [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: 05/29/2023] [Accepted: 01/19/2024] [Indexed: 02/22/2024] Open
Abstract
Myoglobin (Mb) plays an important role at rest and during exercise as a reservoir of oxygen and has been suggested to regulate NO• bioavailability under hypoxic/acidic conditions. However, its ultimate role during exercise is still a subject of debate. We aimed to study the effect of Mb deficiency on maximal oxygen uptake (V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ ) and exercise performance in myoglobin knockout mice (Mb-/- ) when compared to control mice (Mb+/+ ). Furthermore, we also studied NO• bioavailability, assessed as nitrite (NO2 - ) and nitrate (NO3 - ) in the heart, locomotory muscle and in plasma, at rest and during exercise at exhaustion both in Mb-/- and in Mb+/+ mice. The mice performed maximal running incremental exercise on a treadmill with whole-body gas exchange measurements. The Mb-/- mice had lower body mass, heart and hind limb muscle mass (P < 0.001). Mb-/- mice had significantly reduced maximal running performance (P < 0.001).V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ expressed in ml min-1 in Mb-/ - mice was 37% lower than in Mb+/+ mice (P < 0.001) and 13% lower when expressed in ml min-1 kg body mass-1 (P = 0.001). Additionally, Mb-/- mice had significantly lower plasma, heart and locomotory muscle NO2 - levels at rest. During exercise NO2 - increased significantly in the heart and locomotory muscles of Mb-/- and Mb+/+ mice, whereas no significant changes in NO2 - were found in plasma. Our study showed that, contrary to recent suggestions, Mb deficiency significantly impairsV ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ and maximal running performance in mice. KEY POINTS: Myoglobin knockout mice (Mb-/- ) possess lower maximal oxygen uptake (V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ ) and poorer maximal running performance than control mice (Mb+/+ ). Respiratory exchange ratio values at high running velocities in Mb-/- mice are higher than in control mice suggesting a shift in substrate utilization towards glucose metabolism in Mb-/- mice at the same running velocities. Lack of myoglobin lowers basal systemic and muscle NO• bioavailability, but does not affect exercise-induced NO2 - changes in plasma, heart and locomotory muscles. The present study demonstrates that myoglobin is of vital importance forV ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ and maximal running performance as well as explains why previous studies have failed to prove such a role of myoglobin when using the Mb-/- mouse model.
Collapse
Affiliation(s)
- Jerzy A Zoladz
- Chair of Exercise Physiology and Muscle Bioenergetics, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
| | - Marcin Grandys
- Chair of Exercise Physiology and Muscle Bioenergetics, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
| | - Marta Smeda
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Agnieszka Kij
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Anna Kurpinska
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Grzegorz Kwiatkowski
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Janusz Karasinski
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, Poland
| | - Ulrike Hendgen-Cotta
- Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - Stefan Chlopicki
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
- Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
| | - Joanna Majerczak
- Chair of Exercise Physiology and Muscle Bioenergetics, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
| |
Collapse
|
|
14
|
Atta S, Mandal A, Saha R, Majumdar A. Reduction of nitrite to nitric oxide and generation of reactive chalcogen species by mononuclear Fe(II) and Zn(II) complexes of thiolate and selenolate. Dalton Trans 2024; 53:949-965. [PMID: 38126213 DOI: 10.1039/d3dt03768a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
Comparative reactivity of a series of new Zn(II) and Fe(II) compounds, [(Py2ald)M(ER)] (E = S, R = Ph: M = Zn, 1aZn; M = Fe, 1aFe; E = S, R = 2,6-Me2-C6H3: M = Zn, 1bZn; M = Fe, 1bFe; E = Se, R = Ph: M = Zn, 2Zn; M = Fe, 2Fe), and [(Py2ald)M]22+ (M = Zn, 5Zn; M = Fe, 5Fe) is presented. Compound 1aZn could react with nitrite (NO2-) to produce [(Py2ald)Zn(ONO)] (3Zn), which, upon treatment with thiols and PhSeH (proton source), could regenerate either 1aZn/5Zn and 2Zn respectively, along with the production of nitric oxide (NO) where the yield of NO increases in the order tBuSH ≪ PhCH2SH < PhSH < PhSeH. In contrast to this, 1aFe, 2Fe and 5Fe could affect the direct reduction of NO2- in the absence of protons to generate NO and [{(Py2ald)(ONO)Fe}2-μ2-O] (8Fe). Moreover, 8Fe could regenerate 5Fe and 1aFe/2Fe upon treatment with 4 and 6 equiv. of PhEH (E = S/Se), respectively, along with the generation of NO. Finally, a comparative study of the mononuclear Zn(II) and Fe(II) compounds for the transfer of the coordinated thiolate/selenolate and the generation and transfer of reactive sulfur/selenium species (RES-, E = Se, S) to a series of organic substrates has been provided.
Collapse
Affiliation(s)
- Sayan Atta
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Kolkata 700032, West Bengal, India.
| | - Amit Mandal
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Kolkata 700032, West Bengal, India.
| | - Rahul Saha
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Kolkata 700032, West Bengal, India.
| | - Amit Majumdar
- School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Kolkata 700032, West Bengal, India.
| |
Collapse
|
|
15
|
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
|
|
16
|
Xu K, Tang H, Xiong J, Ban X, Duan Y, Tu Y. Tyrosine kinase inhibitors and atherosclerosis: A close but complicated relationship. Eur J Pharmacol 2023:175869. [PMID: 37369295 DOI: 10.1016/j.ejphar.2023.175869] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 06/29/2023]
Abstract
Targeted cancer therapies have revolutionized the treatment of the disease in the past decade. The tyrosine kinase inhibitor (TKI) class of drugs is a widely used option for treating various cancers. Despite numerous advances, clinical and experimental studies have demonstrated the atherosclerosis-inducing properties of these drugs that can cause adverse cardiovascular events. TKIs also have an atherosclerosis-preventing role in patients with cancer through different mechanisms under various conditions, suggesting that specific drugs play different roles in atherosclerosis regulation. Given these contradictory properties, this review summarizes the outcomes of previously performed clinical and basic experiments and shows how the targeted effects of novel TKIs affect atherosclerosis. Future collaborative efforts are warranted to enhance our understanding of the association between TKIs and atherosclerosis.
Collapse
Affiliation(s)
- Ke Xu
- Department of Cardiology, The First Hospital of Harbin Medical University, Youzheng Street 23#, Nangang District, Harbin, 150001, Heilongjiang Province, China
| | - Hao Tang
- Department of Cardiology, The First Hospital of Harbin Medical University, Youzheng Street 23#, Nangang District, Harbin, 150001, Heilongjiang Province, China
| | - Jie Xiong
- Department of Cardiology, The Second Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Xiaofang Ban
- Department of Cardiology, The Second Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Yuchen Duan
- Department of Cardiology, The First Hospital of Harbin Medical University, Youzheng Street 23#, Nangang District, Harbin, 150001, Heilongjiang Province, China
| | - Yingfeng Tu
- Department of Cardiology, The First Hospital of Harbin Medical University, Youzheng Street 23#, Nangang District, Harbin, 150001, Heilongjiang Province, China.
| |
Collapse
|
|
17
|
Ramasamy R, Baker DS, Lemtiri-Chlieh F, Rosenberg DA, Woon E, Al-Naggar IM, Hardy CC, Levine ES, Kuchel GA, Bartley JM, Smith PP. Loss of resilience contributes to detrusor underactivity in advanced age. Biogerontology 2023; 24:163-181. [PMID: 36626035 PMCID: PMC10006334 DOI: 10.1007/s10522-022-10005-y] [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: 11/02/2022] [Accepted: 12/13/2022] [Indexed: 01/11/2023]
Abstract
Volume hyposensitivity resulting from impaired sympathetic detrusor relaxation during bladder filling contributes to detrusor underactivity (DU) associated with aging. Detrusor tension regulation provides an adaptive sensory input of bladder volume to the brainstem and is challenged by physiological stressors superimposed upon biological aging. We recently showed that HCN channels have a stabilizing role in detrusor sympathetic relaxation. While mature mice maintain homeostasis in the face of stressors, old mice are not always capable. In old mice, there is a dichotomous phenotype, in which resilient mice adapt and maintain homeostasis, while non-resilient mice fail to maintain physiologic homeostasis. In this DU model, we used cystometry as a stressor to categorize mice as old-responders (old-R, develop a filling/voiding cycle) or old-non-responders (old-NR, fail to develop a filling/voiding cycle; fluctuating high pressures and continuous leaking), while also assessing functional and molecular differences. Lamotrigine (HCN activator)-induced bladder relaxation is diminished in old-NR mice following HCN-blockade. Relaxation responses to NS 1619 were reduced in old-NR mice, with the effect lost following HCN-blockade. However, RNA-sequencing revealed no differences in HCN gene expression and electrophysiology studies showed similar percentage of detrusor myocytes expressing HCN (Ih) current between old-R and old-NR mice. Our murine model of DU further defines a role for HCN, with failure of adaptive recalibration of HCN participation and intensity of HCN-mediated stabilization, while genomic studies show upregulated myofibroblast and fibrosis pathways and downregulated neurotransmitter-degradation pathways in old-NR mice. Thus, the DU phenotype is multifactorial and represents the accumulation of age-associated loss in homeostatic mechanisms.
Collapse
Affiliation(s)
- Ramalakshmi Ramasamy
- UConn Center on Aging, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-8073, USA
- Connecticut Institute for the Brain and Cognitive Sciences, University of Connecticut, Storrs, CT, USA
- Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Dylan S Baker
- UConn Center on Aging, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-8073, USA
- Department of Genetics and Genome Sciences, Institute for Systems Genomics, University of Connecticut School of Medicine, Farmington, CT, USA
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Fouad Lemtiri-Chlieh
- UConn Center on Aging, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-8073, USA
- Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Dawn A Rosenberg
- UConn Center on Aging, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-8073, USA
- Department of Cell Biology, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Eric Woon
- UConn Center on Aging, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-8073, USA
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, USA
| | - Iman M Al-Naggar
- UConn Center on Aging, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-8073, USA
- Department of Cell Biology, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Cara C Hardy
- UConn Center on Aging, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-8073, USA
- Connecticut Institute for the Brain and Cognitive Sciences, University of Connecticut, Storrs, CT, USA
- Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Eric S Levine
- Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA
| | - George A Kuchel
- UConn Center on Aging, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-8073, USA
| | - Jenna M Bartley
- UConn Center on Aging, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-8073, USA.
- Department of Immunology, University of Connecticut School of Medicine, Farmington, CT, USA.
| | - Phillip P Smith
- UConn Center on Aging, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-8073, USA
- Connecticut Institute for the Brain and Cognitive Sciences, University of Connecticut, Storrs, CT, USA
- Department of Surgery, University of Connecticut School of Medicine, Farmington, CT, USA
- Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA
| |
Collapse
|
|
18
|
Liubertas T, Poderys JL, Zigmantaite V, Viskelis P, Kucinskas A, Grigaleviciute R, Jurevicius J, Urbonaviciene D. The Effect of Potassium Nitrate Supplementation on the Force and Properties of Extensor digitorum longus (EDL) Muscles in Mice. Nutrients 2023; 15:nu15061489. [PMID: 36986219 PMCID: PMC10057731 DOI: 10.3390/nu15061489] [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: 02/21/2023] [Revised: 03/16/2023] [Accepted: 03/17/2023] [Indexed: 03/22/2023] Open
Abstract
Adding potassium nitrate (KNO3) to the diet improves the physiological properties of mammalian muscles (rebuilds weakened muscle, improves structure and functionality). The aim of this study was to investigate the effect of KNO3 supplementation in a mouse model. BALB/c mice were fed a KNO3 diet for three weeks, followed by a normal diet without nitrates. After the feeding period, the Extensor digitorum longus (EDL) muscle was evaluated ex vivo for contraction force and fatigue. To evaluate the possible pathological changes, the histology of EDL tissues was performed in control and KNO3-fed groups after 21 days. The histological analysis showed an absence of negative effects in EDL muscles. We also analyzed 15 biochemical blood parameters. After 21 days of KNO3 supplementation, the EDL mass was, on average, 13% larger in the experimental group compared to the controls (p < 0.05). The muscle-specific force increased by 38% in comparison with the control group (p < 0.05). The results indicate that KNO3 has effects in an experimental mouse model, showing nitrate-diet-induced muscle strength. This study contributes to a better understanding of the molecular changes in muscles following nutritional intervention and may help develop strategies and products designated to treat muscle-related issues.
Collapse
Affiliation(s)
- Tomas Liubertas
- Department of Coaching Science, Lithuanian Sports University, 44221 Kaunas, Lithuania
- Correspondence: ; Tel.: +370-6126-6664
| | - Jonas Liudas Poderys
- Department of Coaching Science, Lithuanian Sports University, 44221 Kaunas, Lithuania
| | - Vilma Zigmantaite
- Biological Research Centre, Lithuanian University of Health Science, 47181 Kaunas, Lithuania
| | - Pranas Viskelis
- Institute of Horticulture, Lithuanian Research Centre for Agriculture and Forestry, 54333 Babtai, Lithuania
| | - Audrius Kucinskas
- Biological Research Centre, Lithuanian University of Health Science, 47181 Kaunas, Lithuania
| | - Ramune Grigaleviciute
- Biological Research Centre, Lithuanian University of Health Science, 47181 Kaunas, Lithuania
| | - Jonas Jurevicius
- Institute of Cardiology, Membrane Biophysics Laboratory, Lithuanian University of Health Sciences, 50162 Kaunas, Lithuania
| | - Dalia Urbonaviciene
- Institute of Horticulture, Lithuanian Research Centre for Agriculture and Forestry, 54333 Babtai, Lithuania
| |
Collapse
|
|
19
|
Keller TCS, Lechauve C, Keller AS, Broseghini-Filho GB, Butcher JT, Askew Page HR, Islam A, Tan ZY, DeLalio LJ, Brooks S, Sharma P, Hong K, Xu W, Padilha AS, Ruddiman CA, Best AK, Macal E, Kim-Shapiro DB, Christ G, Yan Z, Cortese-Krott MM, Ricart K, Patel R, Bender TP, Sonkusare SK, Weiss MJ, Ackerman H, Columbus L, Isakson BE. Endothelial alpha globin is a nitrite reductase. Nat Commun 2022; 13:6405. [PMID: 36302779 PMCID: PMC9613979 DOI: 10.1038/s41467-022-34154-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 10/04/2022] [Indexed: 01/29/2023] Open
Abstract
Resistance artery vasodilation in response to hypoxia is essential for matching tissue oxygen and demand. In hypoxia, erythrocytic hemoglobin tetramers produce nitric oxide through nitrite reduction. We hypothesized that the alpha subunit of hemoglobin expressed in endothelium also facilitates nitrite reduction proximal to smooth muscle. Here, we create two mouse strains to test this: an endothelial-specific alpha globin knockout (EC Hba1Δ/Δ) and another with an alpha globin allele mutated to prevent alpha globin's inhibitory interaction with endothelial nitric oxide synthase (Hba1WT/Δ36-39). The EC Hba1Δ/Δ mice had significantly decreased exercise capacity and intracellular nitrite consumption in hypoxic conditions, an effect absent in Hba1WT/Δ36-39 mice. Hypoxia-induced vasodilation is significantly decreased in arteries from EC Hba1Δ/Δ, but not Hba1WT/Δ36-39 mice. Hypoxia also does not lower blood pressure in EC Hba1Δ/Δ mice. We conclude the presence of alpha globin in resistance artery endothelium acts as a nitrite reductase providing local nitric oxide in response to hypoxia.
Collapse
Affiliation(s)
- T C Stevenson Keller
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Christophe Lechauve
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Alexander S Keller
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Gilson Brás Broseghini-Filho
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Physiological Sciences, Federal University of Espirito Santo, Vitória, Brazil
| | - Joshua T Butcher
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA
| | - Henry R Askew Page
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Aditi Islam
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Zhe Yin Tan
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Leon J DeLalio
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Steven Brooks
- Physiology Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
| | - Poonam Sharma
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Kwangseok Hong
- Department of Physical Education, College of Education, Chung-Ang University, Seoul, South Korea
| | - Wenhao Xu
- Transgenic Mouse Facility, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA
| | | | - Claire A Ruddiman
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Angela K Best
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Edgar Macal
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Daniel B Kim-Shapiro
- Department of Physics, Translational Science Center, Wake Forest University, Winston-Salem, NC, USA
| | - George Christ
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Zhen Yan
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Miriam M Cortese-Krott
- Cardiovascular Research Laboratory, Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Karina Ricart
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rakesh Patel
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Timothy P Bender
- Department of Microbiology, Immunology and Cancer, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Swapnil K Sonkusare
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Mitchell J Weiss
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Hans Ackerman
- Physiology Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
| | - Linda Columbus
- Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Chemistry, University of Virginia, Charlottesville, VA, USA
| | - Brant E Isakson
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA.
- Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, VA, USA.
| |
Collapse
|
|
20
|
Wang F, Qin K, Wang K, Wang H, Liu Q, Qian M, Chen S, Sun Y, Hou J, Wei Y, Hu Y, Li Z, Xu Q, Zhao Q. Nitric oxide improves regeneration and prevents calcification in bio-hybrid vascular grafts via regulation of vascular stem/progenitor cells. Cell Rep 2022; 39:110981. [PMID: 35732119 DOI: 10.1016/j.celrep.2022.110981] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 04/29/2022] [Accepted: 05/28/2022] [Indexed: 11/18/2022] Open
Abstract
Vascular bypass surgery continues to use autologous grafts and often suffers from a shortage of donor grafts. Decellularized xenografts derived from porcine veins provide a promising candidate because of their abundant availability and low immunogenicity. Unfortunately, transplantation outcomes are far from satisfactory because of insufficient regeneration and adverse pathologic remodeling. Herein, a nitrate-functionalized prosthesis has been incorporated into a decellularized porcine vein graft to fabricate a bio-hybrid vascular graft with local delivery of nitric oxide (NO). Exogenous NO efficiently promotes vascular regeneration and attenuates intimal hyperplasia and vascular calcification in both rabbit and mouse models. The underlying mechanism was investigated using a Sca1 2A-CreER; Rosa-RFP genetic-lineage-tracing mouse model that reveals that Sca1+ stem/progenitor cells (SPCs) are major contributors to vascular regeneration and remodeling, and NO plays a critical role in regulating SPC fate. These results support the translational potential of this off-the-shelf vascular graft.
Collapse
Affiliation(s)
- Fei Wang
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China; Medical Research Center, Binzhou Medical University Hospital, Binzhou 256600, China
| | - Kang Qin
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Kai Wang
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - He Wang
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Qi Liu
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Meng Qian
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Shang Chen
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Yijin Sun
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Jingli Hou
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Yongzhen Wei
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Yanhua Hu
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China
| | - Zongjin Li
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Qingbo Xu
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China.
| | - Qiang Zhao
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China.
| |
Collapse
|
|
21
|
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
|
|
22
|
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
|
|
23
|
Nitrite Concentration in the Striated Muscles Is Reversely Related to Myoglobin and Mitochondrial Proteins Content in Rats. Int J Mol Sci 2022; 23:ijms23052686. [PMID: 35269826 PMCID: PMC8910716 DOI: 10.3390/ijms23052686] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 02/21/2022] [Accepted: 02/27/2022] [Indexed: 12/12/2022] Open
Abstract
Skeletal muscles are an important reservoir of nitric oxide (NO•) stored in the form of nitrite [NO2−] and nitrate [NO3−] (NOx). Nitrite, which can be reduced to NO• under hypoxic and acidotic conditions, is considered a physiologically relevant, direct source of bioactive NO•. The aim of the present study was to determine the basal levels of NOx in striated muscles (including rat heart and locomotory muscles) with varied contents of tissue nitrite reductases, such as myoglobin and mitochondrial electron transport chain proteins (ETC-proteins). Muscle NOx was determined using a high-performance liquid chromatography-based method. Muscle proteins were evaluated using western-immunoblotting. We found that oxidative muscles with a higher content of ETC-proteins and myoglobin (such as the heart and slow-twitch locomotory muscles) have lower [NO2−] compared to fast-twitch muscles with a lower content of those proteins. The muscle type had no observed effect on the [NO3−]. Our results demonstrated that fast-twitch muscles possess greater potential to generate NO• via nitrite reduction than slow-twitch muscles and the heart. This property might be of special importance for fast skeletal muscles during strenuous exercise and/or hypoxia since it might support muscle blood flow via additional NO• provision (acidic/hypoxic vasodilation) and delay muscle fatigue.
Collapse
|
|
24
|
Chung CW, Liao BW, Huang SW, Chiou SJ, Chang CH, Lin SJ, Chen BH, Liu WL, Hu SH, Chuang YC, Lin CH, Hsu IJ, Cheng CM, Huang CC, Lu TT. Magnetic Responsive Release of Nitric Oxide from an MOF-Derived Fe 3O 4@PLGA Microsphere for the Treatment of Bacteria-Infected Cutaneous Wound. ACS APPLIED MATERIALS & INTERFACES 2022; 14:6343-6357. [PMID: 35080366 DOI: 10.1021/acsami.1c20802] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Nitric oxide (NO) is an essential endogenous signaling molecule regulating multifaceted physiological functions in the (cardio)vascular, neuronal, and immune systems. Due to the short half-life and location-/concentration-dependent physiological function of NO, translational application of NO as a novel therapeutic approach, however, awaits a strategy for spatiotemporal control on the delivery of NO. Inspired by the magnetic hyperthermia and magneto-triggered drug release featured by Fe3O4 conjugates, in this study, we aim to develop a magnetic responsive NO-release material (MagNORM) featuring dual NO-release phases, namely, burst and steady release, for the selective activation of NO-related physiology and treatment of bacteria-infected cutaneous wound. After conjugation of NO-delivery [Fe(μ-S-thioglycerol)(NO)2]2 with a metal-organic framework (MOF)-derived porous Fe3O4@C, encapsulation of obtained conjugates within the thermo-responsive poly(lactic-co-glycolic acid) (PLGA) microsphere completes the assembly of MagNORM. Through continuous/pulsatile/no application of the alternating magnetic field (AMF) to MagNORM, moreover, burst/intermittent/slow release of NO from MagNORM demonstrates the AMF as an ON/OFF switch for temporal control on the delivery of NO. Under continuous application of the AMF, in particular, burst release of NO from MagNORM triggers an effective anti-bacterial activity against both Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli). In addition to the magneto-triggered bactericidal effect of MagNORM against E. coli-infected cutaneous wound in mice, of importance, steady release of NO from MagNORM without the AMF promotes the subsequent collagen formation and wound healing in mice.
Collapse
Affiliation(s)
- Chieh-Wei Chung
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Bo-Wen Liao
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Shu-Wei Huang
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Show-Jen Chiou
- Department of Applied Chemistry, National Chiayi University, Chiayi 60004, Taiwan
| | - Cheng-Han Chang
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Sheng-Ju Lin
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Bo-Hao Chen
- National Synchrotron Radiation Research Center, Hsinchu 30076, Taiwan
| | - Wei-Ling Liu
- Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan
| | - Shang-Hsiu Hu
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Yu-Chun Chuang
- National Synchrotron Radiation Research Center, Hsinchu 30076, Taiwan
| | - Chia-Her Lin
- Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan
| | - I-Jui Hsu
- Department of Molecular Science and Engineering, Research and Development Center of Smart Textile Technology, National Taipei University of Technology, Taipei 10608, Taiwan
| | - Chao-Min Cheng
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Chieh-Cheng Huang
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Tsai-Te Lu
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
| |
Collapse
|
|
25
|
Courand PY, Berger M, Bouali A, Harbaoui B, Lantelme P, Dalle S. Cardiac Effects of BRAF and MEK Inhibitors: Mechanisms and Clinical Management. Curr Oncol Rep 2022; 24:265-271. [PMID: 35102484 DOI: 10.1007/s11912-022-01205-3] [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] [Accepted: 10/07/2021] [Indexed: 11/28/2022]
Abstract
PURPOSE OF REVIEW The identification of BRAF mutation prompted the development of new class of targeted therapy for treating melanoma: BRAF inhibitors and MEK inhibitors. Cardiovascular events have been reported with these treatments and could counterbalance their long-term maintenance. RECENT FINDINGS LVEF decrease due to BRAF and MEK inhibitors appears fairly common (10%) but usually not severe, without impact on patient outcomes. To date, no treatment options have been tested to prevent or to treat a decrease of LVEF associated with BRAF and MEK inhibitors. QTc prolongation was observed in 3% and arterial hypertension in 20% during treatment but only one-third of cases required a therapeutic change. BRAF and MEK inhibitors have revolutionized the management and the prognosis of melanoma patients. Cardio-oncology units may be useful for a better care of potential cardiac toxicity and particularly to inappropriately avoid discontinuing BRAF and MEK inhibitors.
Collapse
Affiliation(s)
- Pierre-Yves Courand
- Fédération de Cardiologie, Hôpital de La Croix-Rousse Et Hôpital Lyon Sud, Hospices Civils de Lyon, 103 Grande Rue de la Croix-Rousse, 69004, Lyon, France. .,Université de Lyon, CREATIS, CNRS UMR5220, INSERM U1044, INSA-Lyon, Université Claude Bernard Lyon 1, Villeurbanne, France.
| | - Mathilde Berger
- Service de Dermatologie, Hôpital de Lyon Sud, Pierre Bénite, France
| | - Anissa Bouali
- Fédération de Cardiologie, Hôpital de La Croix-Rousse Et Hôpital Lyon Sud, Hospices Civils de Lyon, 103 Grande Rue de la Croix-Rousse, 69004, Lyon, France
| | - Brahim Harbaoui
- Fédération de Cardiologie, Hôpital de La Croix-Rousse Et Hôpital Lyon Sud, Hospices Civils de Lyon, 103 Grande Rue de la Croix-Rousse, 69004, Lyon, France.,Université de Lyon, CREATIS, CNRS UMR5220, INSERM U1044, INSA-Lyon, Université Claude Bernard Lyon 1, Villeurbanne, France
| | - Pierre Lantelme
- Fédération de Cardiologie, Hôpital de La Croix-Rousse Et Hôpital Lyon Sud, Hospices Civils de Lyon, 103 Grande Rue de la Croix-Rousse, 69004, Lyon, France.,Université de Lyon, CREATIS, CNRS UMR5220, INSERM U1044, INSA-Lyon, Université Claude Bernard Lyon 1, Villeurbanne, France
| | - Stéphane Dalle
- Service de Dermatologie, Hôpital de Lyon Sud, Pierre Bénite, France
| |
Collapse
|
|
26
|
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: 132] [Impact Index Per Article: 33.0] [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
|
|
27
|
Leo F, Suvorava T, Heuser SK, Li J, LoBue A, Barbarino F, Piragine E, Schneckmann R, Hutzler B, Good ME, Fernandez BO, Vornholz L, Rogers S, Doctor A, Grandoch M, Stegbauer J, Weitzberg E, Feelisch M, Lundberg JO, Isakson BE, Kelm M, Cortese-Krott MM. Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure. Circulation 2021; 144:870-889. [PMID: 34229449 PMCID: PMC8529898 DOI: 10.1161/circulationaha.120.049606] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 06/22/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND Current paradigms suggest that nitric oxide (NO) produced by endothelial cells (ECs) through endothelial nitric oxide synthase (eNOS) in the vessel wall is the primary regulator of blood flow and blood pressure. However, red blood cells (RBCs) also carry a catalytically active eNOS, but its role is controversial and remains undefined. This study aimed to elucidate the functional significance of RBC eNOS compared with EC eNOS for vascular hemodynamics and nitric oxide metabolism. METHODS We generated tissue-specific loss- and gain-of-function models for eNOS by using cell-specific Cre-induced gene inactivation or reactivation. We created 2 founder lines carrying a floxed eNOS (eNOSflox/flox) for Cre-inducible knockout (KO), and gene construct with an inactivated floxed/inverted exon (eNOSinv/inv) for a Cre-inducible knock-in (KI), which respectively allow targeted deletion or reactivation of eNOS in erythroid cells (RBC eNOS KO or RBC eNOS KI mice) or in ECs (EC eNOS KO or EC eNOS KI mice). Vascular function, hemodynamics, and nitric oxide metabolism were compared ex vivo and in vivo. RESULTS The EC eNOS KOs exhibited significantly impaired aortic dilatory responses to acetylcholine, loss of flow-mediated dilation, and increased systolic and diastolic blood pressure. RBC eNOS KO mice showed no alterations in acetylcholine-mediated dilation or flow-mediated dilation but were hypertensive. Treatment with the nitric oxide synthase inhibitor Nγ-nitro-l-arginine methyl ester further increased blood pressure in RBC eNOS KOs, demonstrating that eNOS in both ECs and RBCs contributes to blood pressure regulation. Although both EC eNOS KOs and RBC eNOS KOs had lower plasma nitrite and nitrate concentrations, the levels of bound NO in RBCs were lower in RBC eNOS KOs than in EC eNOS KOs. Reactivation of eNOS in ECs or RBCs rescues the hypertensive phenotype of the eNOSinv/inv mice, whereas the levels of bound NO were restored only in RBC eNOS KI mice. CONCLUSIONS These data reveal that eNOS in ECs and RBCs contribute independently to blood pressure homeostasis.
Collapse
Affiliation(s)
- Francesca Leo
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology (F.L., T.S., S.K.H., J.L., A.L.B., F.B., E.P., B.H., L.V., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Tatsiana Suvorava
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology (F.L., T.S., S.K.H., J.L., A.L.B., F.B., E.P., B.H., L.V., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
- Department of Cardiology Pneumology and Angiology (T.S., M.K., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Sophia K. Heuser
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology (F.L., T.S., S.K.H., J.L., A.L.B., F.B., E.P., B.H., L.V., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Junjie Li
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology (F.L., T.S., S.K.H., J.L., A.L.B., F.B., E.P., B.H., L.V., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Anthea LoBue
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology (F.L., T.S., S.K.H., J.L., A.L.B., F.B., E.P., B.H., L.V., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Frederik Barbarino
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology (F.L., T.S., S.K.H., J.L., A.L.B., F.B., E.P., B.H., L.V., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
- Department of Pharmacy, University of Pisa, Italy (F.P.)
| | - Eugenia Piragine
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology (F.L., T.S., S.K.H., J.L., A.L.B., F.B., E.P., B.H., L.V., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Rebekka Schneckmann
- Department of Pharmacology and Clinical Pharmacology (R.S., M.G.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Beate Hutzler
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology (F.L., T.S., S.K.H., J.L., A.L.B., F.B., E.P., B.H., L.V., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Miranda E. Good
- Robert M. Berne Cardiovascular Research Center, Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville (M.E.G., B.E.I.)
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (M.E.G.)
| | - Bernadette O. Fernandez
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, United Kingdom (B.O.F.)
| | - Lukas Vornholz
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology (F.L., T.S., S.K.H., J.L., A.L.B., F.B., E.P., B.H., L.V., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Stephen Rogers
- Department of Pediatrics, Center for Blood Oxygen Transport and Hemostasis, University of Maryland School of Medicine, Baltimore (S.R., A.D.)
| | - Allan Doctor
- Department of Pediatrics, Center for Blood Oxygen Transport and Hemostasis, University of Maryland School of Medicine, Baltimore (S.R., A.D.)
| | - Maria Grandoch
- Department of Pharmacology and Clinical Pharmacology (R.S., M.G.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Johannes Stegbauer
- Department of Nephrology (J.S.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Eddie Weitzberg
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (E.W., J.O.L., M.M.C.-K.)
| | - Martin Feelisch
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology (F.L., T.S., S.K.H., J.L., A.L.B., F.B., E.P., B.H., L.V., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
- Department of Pharmacology and Clinical Pharmacology (R.S., M.G.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
- Department of Nephrology (J.S.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
- Department of Cardiology Pneumology and Angiology (T.S., M.K., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
- CARID, Cardiovascular Research Institute Düsseldorf (M.K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
- Department of Pharmacy, University of Pisa, Italy (F.P.)
- Robert M. Berne Cardiovascular Research Center, Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville (M.E.G., B.E.I.)
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (M.E.G.)
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, United Kingdom (B.O.F.)
- Department of Pediatrics, Center for Blood Oxygen Transport and Hemostasis, University of Maryland School of Medicine, Baltimore (S.R., A.D.)
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (E.W., J.O.L., M.M.C.-K.)
| | - Jon O. Lundberg
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (E.W., J.O.L., M.M.C.-K.)
| | - Brant E. Isakson
- Robert M. Berne Cardiovascular Research Center, Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville (M.E.G., B.E.I.)
| | - Malte Kelm
- Department of Cardiology Pneumology and Angiology (T.S., M.K., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
- CARID, Cardiovascular Research Institute Düsseldorf (M.K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Miriam M. Cortese-Krott
- Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology (F.L., T.S., S.K.H., J.L., A.L.B., F.B., E.P., B.H., L.V., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
- Department of Cardiology Pneumology and Angiology (T.S., M.K., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (E.W., J.O.L., M.M.C.-K.)
| |
Collapse
|
|
28
|
Kirby BS, Sparks MA, Lazarowski ER, Lopez Domowicz DA, Zhu H, McMahon TJ. Pannexin 1 channels control the hemodynamic response to hypoxia by regulating O 2-sensitive extracellular ATP in blood. Am J Physiol Heart Circ Physiol 2021; 320:H1055-H1065. [PMID: 33449849 PMCID: PMC7988759 DOI: 10.1152/ajpheart.00651.2020] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 01/07/2021] [Accepted: 01/07/2021] [Indexed: 12/23/2022]
Abstract
Pannexin 1 (Panx1) channels export ATP and may contribute to increased concentration of the vasodilator ATP in plasma during hypoxia in vivo. We hypothesized that Panx1 channels and associated ATP export contribute to hypoxic vasodilation, a mechanism that facilitates the matching of oxygen delivery to metabolic demand of tissue. Male and female mice devoid of Panx1 (Panx1-/-) and wild-type controls (WT) were anesthetized, mechanically ventilated, and instrumented with a carotid artery catheter or femoral artery flow transducer for hemodynamic and plasma ATP monitoring during inhalation of 21% (normoxia) or 10% oxygen (hypoxia). ATP export from WT vs. Panx1-/-erythrocytes (RBC) was determined ex vivo via tonometer experimentation across progressive deoxygenation. Mean arterial pressure (MAP) was similar in Panx1-/- (n = 6) and WT (n = 6) mice in normoxia, but the decrease in MAP in hypoxia seen in WT was attenuated in Panx1-/- mice (-16 ± 9% vs. -2 ± 8%; P < 0.05). Hindlimb blood flow (HBF) was significantly lower in Panx1-/- (n = 6) vs. WT (n = 6) basally, and increased in WT but not Panx1-/- mice during hypoxia (8 ± 6% vs. -10 ± 13%; P < 0.05). Estimation of hindlimb vascular conductance using data from the MAP and HBF experiments showed an average response of 28% for WT vs. -9% for Panx1-/- mice. Mean venous plasma ATP during hypoxia was 57% lower in Panx1-/- (n = 6) vs. WT mice (n = 6; P < 0.05). Mean hypoxia-induced ATP export from RBCs from Panx1-/- mice (n = 8) was 82% lower than that from WT (n = 8; P < 0.05). Panx1 channels participate in hemodynamic responses consistent with hypoxic vasodilation by regulating hypoxia-sensitive extracellular ATP levels in blood.NEW & NOTEWORTHY Export of vasodilator ATP from red blood cells requires pannexin 1. Blood plasma ATP elevations in response to hypoxia in mice require pannexin 1. Hemodynamic responses to hypoxia are accompanied by increased plasma ATP in mice in vivo and require pannexin 1.
Collapse
Affiliation(s)
- Brett S Kirby
- Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Matthew A Sparks
- Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina
- Departments of Medicine and Research and Development, Durham Veterans Affairs Medical Center, Durham, North Carolina
| | - Eduardo R Lazarowski
- Department of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina
| | - Denise A Lopez Domowicz
- Division of Critical Care Medicine, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina
| | - Hongmei Zhu
- Division of Pulmonary, Allergy, Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Timothy J McMahon
- Department of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina
- Division of Pulmonary, Allergy, Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina
| |
Collapse
|
|
29
|
Berenbrink M. The role of myoglobin in the evolution of mammalian diving capacity – The August Krogh principle applied in molecular and evolutionary physiology. Comp Biochem Physiol A Mol Integr Physiol 2021; 252:110843. [DOI: 10.1016/j.cbpa.2020.110843] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 11/06/2020] [Indexed: 01/21/2023]
|
|
30
|
Cialoni D, Brizzolari A, Samaja M, Bosco G, Paganini M, Pieri M, Lancellotti V, Marroni A. Nitric Oxide and Oxidative Stress Changes at Depth in Breath-Hold Diving. Front Physiol 2021; 11:609642. [PMID: 33488400 PMCID: PMC7818785 DOI: 10.3389/fphys.2020.609642] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/01/2020] [Indexed: 12/14/2022] Open
Abstract
Background Several mechanisms allow humans to resist the extreme conditions encountered during breath-hold diving. Available nitric oxide (NO) is one of the major contributors to such complex adaptations at depth and oxidative stress is one of the major collateral effects of diving. Due to technical difficulties, these biomarkers have not so far been studied in vivo while at depth. The aim of this study is to investigate nitrate and nitrite (NOx) concentration, total antioxidant capacity (TAC) and lipid peroxidation (TBARS) before, during, and after repetitive breath-hold dives in healthy volunteers. Materials and Methods Blood plasma, obtained from 14 expert breath-hold divers, was tested for differences in NOx, TAC, and TBARS between pre-dive, bottom, surface, 30 and 60 min post-dive samples. Results We observed a statistically significant increase of NOx plasma concentration in the “bottom blood draw” as compared to the pre-dive condition while we did not find any difference in the following samples We found a statistically significant decrease in TAC at the bottom but the value returned to normality immediately after reaching the surface. We did not find any statistically significant difference in TBARS. Discussion The increased plasma NOx values found at the bottom were not observed at surface and post dive sampling (T0, T30, T60), showing a very rapid return to the pre-dive values. Also TAC values returned to pre- diving levels immediately after the end of hyperbaric exposure, probably as a consequence of the activation of endogenous antioxidant defenses. TBARS did not show any difference during the protocol.
Collapse
Affiliation(s)
- Danilo Cialoni
- Environmental Physiology and Medicine Laboratory, Department of Biomedical Sciences, University of Padova, Padova, Italy.,Divers Alert Network (DAN) Europe Research Division, Roseto degli Abruzzi, Italy.,Apnea Academy Research, Padova, Italy
| | - Andrea Brizzolari
- Divers Alert Network (DAN) Europe Research Division, Roseto degli Abruzzi, Italy.,Department of Health Sciences, Università degli Studi of Milan, Milan, Italy
| | - Michele Samaja
- Department of Health Sciences, Università degli Studi of Milan, Milan, Italy
| | - Gerardo Bosco
- Environmental Physiology and Medicine Laboratory, Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Matteo Paganini
- Environmental Physiology and Medicine Laboratory, Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Massimo Pieri
- Divers Alert Network (DAN) Europe Research Division, Roseto degli Abruzzi, Italy
| | - Valentina Lancellotti
- Cardiothoracic and Vascular Department, Azienda Ospedaliero-Universitaria Pisana (AOUP), Pisa, Italy
| | - Alessandro Marroni
- Divers Alert Network (DAN) Europe Research Division, Roseto degli Abruzzi, Italy
| |
Collapse
|
|
31
|
Pregnant alpha-1-microglobulin (A1M) knockout mice exhibit features of kidney and placental damage, hemodynamic changes and intrauterine growth restriction. Sci Rep 2020; 10:20625. [PMID: 33244052 PMCID: PMC7691512 DOI: 10.1038/s41598-020-77561-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 11/11/2020] [Indexed: 11/09/2022] Open
Abstract
Alpha-1-microglobulin (A1M) is an antioxidant previously shown to be elevated in maternal blood during pregnancies complicated by preeclampsia and suggested to be important in the endogenous defense against oxidative stress. A knockout mouse model of A1M (A1Mko) was used in the present study to assess the importance of A1M during pregnancy in relation to the kidney, heart and placenta function. Systolic blood pressure (SBP) and heart rate (HR) were determined before and throughout gestation. The morphology of the organs was assessed by both light and electron microscopy. Gene expression profiles relating to vascular tone and oxidative stress were analyzed using RT-qPCR with validation of selected gene expression relating to vascular tone and oxidative stress response. Pregnant age-matched wild type mice were used as controls. In the A1Mko mice there was a significantly higher SBP before pregnancy that during pregnancy was significantly reduced compared to the control. In addition, the HR was higher both before and during pregnancy compared to the controls. Renal morphological abnormalities were more frequent in the A1Mko mice, and the gene expression profiles in the kidney and the heart showed downregulation of transcripts associated with vasodilation. Simultaneously, an upregulation of vasoconstrictors, blood pressure regulators, and genes for osmotic stress response, ion transport and reactive oxygen species (ROS) metabolism occurred. Fetal weight was lower in the A1Mko mice at E17.5. The vessels in the labyrinth zone of the placentas and the endoplasmic reticulum in the spongiotrophoblasts were collapsed. The gene profiles in the placenta showed downregulation of antioxidants, ROS metabolism and oxidative stress response genes. In conclusion, intact A1M expression is necessary for the maintenance of normal kidney, heart as well as placental structure and function for a normal pregnancy adaptation.
Collapse
|
|
32
|
Yang M, Dart C, Kamishima T, Quayle JM. Hypoxia and metabolic inhibitors alter the intracellular ATP:ADP ratio and membrane potential in human coronary artery smooth muscle cells. PeerJ 2020; 8:e10344. [PMID: 33240653 PMCID: PMC7664465 DOI: 10.7717/peerj.10344] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 10/20/2020] [Indexed: 11/20/2022] Open
Abstract
ATP-sensitive potassium (KATP) channels couple cellular metabolism to excitability, making them ideal candidate sensors for hypoxic vasodilation. However, it is still unknown whether cellular nucleotide levels are affected sufficiently to activate vascular KATP channels during hypoxia. To address this fundamental issue, we measured changes in the intracellular ATP:ADP ratio using the biosensors Perceval/PercevalHR, and membrane potential using the fluorescent probe DiBAC4(3) in human coronary artery smooth muscle cells (HCASMCs). ATP:ADP ratio was significantly reduced by exposure to hypoxia. Application of metabolic inhibitors for oxidative phosphorylation also reduced ATP:ADP ratio. Hyperpolarization caused by inhibiting oxidative phosphorylation was blocked by either 10 µM glibenclamide or 60 mM K+. Hyperpolarization caused by hypoxia was abolished by 60 mM K+ but not by individual K+ channel inhibitors. Taken together, these results suggest hypoxia causes hyperpolarization in part by modulating K+ channels in SMCs.
Collapse
Affiliation(s)
- Mingming Yang
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, People’s Republic of China
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, Liverpool, UK
| | - Caroline Dart
- Department of Biochemistry, Institute of Integrative Biology, Liverpool, UK
| | - Tomoko Kamishima
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, Liverpool, UK
| | - John M. Quayle
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, Liverpool, UK
| |
Collapse
|
|
33
|
Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport. Redox Biol 2020; 37:101687. [PMID: 32863222 PMCID: PMC7475203 DOI: 10.1016/j.redox.2020.101687] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 08/11/2020] [Accepted: 08/11/2020] [Indexed: 12/16/2022] Open
Abstract
Vertebrate hemoglobin (Hb) and myoglobin (Mb) were among the first proteins whose structures and sequences were determined over 50 years ago. In the subsequent pregenomic period, numerous related proteins came to light in plants, invertebrates and bacteria, that shared the myoglobin fold, a signature sequence motif characteristic of a 3-on-3 α-helical sandwich. Concomitantly, eukaryote and bacterial globins with a truncated 2-on-2 α-helical fold were discovered. Genomic information over the last 20 years has dramatically expanded the list of known globins, demonstrating their existence in a limited number of archaeal genomes, a majority of bacterial genomes and an overwhelming majority of eukaryote genomes. In vertebrates, 6 additional globin types were identified, namely neuroglobin (Ngb), cytoglobin (Cygb), globin E (GbE), globin X (GbX), globin Y (GbY) and androglobin (Adgb). Furthermore, functions beyond the familiar oxygen transport and storage have been discovered within the vertebrate globin family, including NO metabolism, peroxidase activity, scavenging of free radicals, and signaling functions. The extension of the knowledge on globin functions suggests that the original roles of bacterial globins must have been enzymatic, involved in defense against NO toxicity, and perhaps also as sensors of O2, regulating taxis away or towards high O2 concentrations. In this review, we aimed to discuss the evolution and remarkable functional diversity of vertebrate globins with particular focus on the variety of non-canonical expression sites of mammalian globins and their according impressive variability of atypical functions.
Collapse
|
|
34
|
Liubertas T, Kairaitis R, Stasiule L, Capkauskiene S, Stasiulis A, Viskelis P, Viškelis J, Urbonaviciene D. The influence of amaranth (Amaranthus hypochondriacus) dietary nitrates on the aerobic capacity of physically active young persons. J Int Soc Sports Nutr 2020; 17:37. [PMID: 32660566 PMCID: PMC7359009 DOI: 10.1186/s12970-020-00366-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 06/30/2020] [Indexed: 11/10/2022] Open
Abstract
Background Recent evidence indicates that elevating plasma nitrites through dietary nitrates (NO3−) supplementation is associated with enhanced muscle efficiency, fatigue resistance and performance. Beetroot (in various forms) is the dominant source of dietary NO3− primarily due to its vast availability and the simple form of preparation suitable for final consumption. After a few years of research and experimentation, our scientific team identified alternative source rich with dietary NO3− as possible nitric oxide precursor, amaranth (Amaranthus hypochondriacus) with a standardized concentration 9–11% of NO3−. This study aimed to evaluate the effect of single-dose (±400 mg of dietary NO3−) and long-term (6 days) supplementation of amaranth concentrate derived dietary NO3− on aerobic capacity in physically active young people. Methods We conducted a randomized, double-blind, placebo-controlled human study. Thirteen healthy and physically active young male participants were randomized into experimental and placebo groups. The aerobic capacity was tested during increasing cycling exercise (ICE) with pulmonary gas exchange recording and analysis. Results The peak power of the ICE, the maximum oxygen consumption and the first ventilatory threshold were significantly increased after long-term consumption of dietary amaranth (from 4.44 ± 0.50 to 4.55 ± 0.43 W/kg; from 37.7 ± 2.7 to 41.2 ± 5.4 mL/kg/min and from 178.6 ± 30.3 to 188.6 ± 35.2 W, p < 0.05; respectively) in experimental group. Conclusions Long-term (6 days) use of dietary NO3− from amaranth may improve the aerobic capacity during ICE in young physically active male persons. It can be recommended as the nutritional supplement during last week of preparation for competition in endurance events.
Collapse
Affiliation(s)
- Tomas Liubertas
- Department of Coaching Science, Lithuanian Sports University, 44221, Kaunas, Lithuania.
| | - Ramutis Kairaitis
- Department of Coaching Science, Lithuanian Sports University, 44221, Kaunas, Lithuania
| | - Loreta Stasiule
- Department of Applied Biology and Rehabilitation, Lithuanian Sports University, 44221, Kaunas, Lithuania
| | - Sandrija Capkauskiene
- Department of Applied Biology and Rehabilitation, Lithuanian Sports University, 44221, Kaunas, Lithuania
| | - Arvydas Stasiulis
- Department of Applied Biology and Rehabilitation, Lithuanian Sports University, 44221, Kaunas, Lithuania
| | - Pranas Viskelis
- Institute of Horticulture, Lithuanian Research Centre for Agriculture and Forestry, 54333, Babtai, Lithuania
| | - Jonas Viškelis
- Institute of Horticulture, Lithuanian Research Centre for Agriculture and Forestry, 54333, Babtai, Lithuania
| | - Dalia Urbonaviciene
- Institute of Horticulture, Lithuanian Research Centre for Agriculture and Forestry, 54333, Babtai, Lithuania
| |
Collapse
|
|
35
|
Kapil V, Khambata RS, Jones DA, Rathod K, Primus C, Massimo G, Fukuto JM, Ahluwalia A. The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway. Pharmacol Rev 2020; 72:692-766. [PMID: 32576603 DOI: 10.1124/pr.120.019240] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
In contrast to nitric oxide, which has well established and important roles in the regulation of blood flow and thrombosis, neurotransmission, the normal functioning of the genitourinary system, and the inflammation response and host defense, its oxidized metabolites nitrite and nitrate have, until recently, been considered to be relatively inactive. However, this view has been radically revised over the past decade and more. Much evidence has now accumulated demonstrating that nitrite serves as a storage form of nitric oxide, releasing nitric oxide preferentially under acidic and/or hypoxic conditions but also occurring under physiologic conditions: a phenomenon that is catalyzed by a number of distinct mammalian nitrite reductases. Importantly, preclinical studies demonstrate that reduction of nitrite to nitric oxide results in a number of beneficial effects, including vasodilatation of blood vessels and lowering of blood pressure, as well as cytoprotective effects that limit the extent of damage caused by an ischemia/reperfusion insult, with this latter issue having been translated more recently to the clinical setting. In addition, research has demonstrated that the other main metabolite of the oxidation of nitric oxide (i.e., nitrate) can also be sequentially reduced through processing in vivo to nitrite and then nitrite to nitric oxide to exert a range of beneficial effects-most notably lowering of blood pressure, a phenomenon that has also been confirmed recently to be an effective method for blood pressure lowering in patients with hypertension. This review will provide a detailed description of the pathways involved in the bioactivation of both nitrate and nitrite in vivo, their functional effects in preclinical models, and their mechanisms of action, as well as a discussion of translational exploration of this pathway in diverse disease states characterized by deficiencies in bioavailable nitric oxide. SIGNIFICANCE STATEMENT: The past 15 years has seen a major revision in our understanding of the pathways for nitric oxide synthesis in the body with the discovery of the noncanonical pathway for nitric oxide generation known as the nitrate-nitrite-nitric oxide pathway. This review describes the molecular components of this pathway, its role in physiology, potential therapeutics of targeting this pathway, and their impact in experimental models, as well as the clinical translation (past and future) and potential side effects.
Collapse
Affiliation(s)
- V Kapil
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - R S Khambata
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - D A Jones
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - K Rathod
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - C Primus
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - G Massimo
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - J M Fukuto
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - A Ahluwalia
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| |
Collapse
|
|
36
|
Mathai C, Jourd'heuil FL, Lopez-Soler RI, Jourd'heuil D. Emerging perspectives on cytoglobin, beyond NO dioxygenase and peroxidase. Redox Biol 2020; 32:101468. [PMID: 32087552 PMCID: PMC7033357 DOI: 10.1016/j.redox.2020.101468] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/05/2020] [Accepted: 02/13/2020] [Indexed: 12/18/2022] Open
Abstract
Cytoglobin is an evolutionary ancient hemoglobin with poor functional annotation. Rather than constrained to penta coordination, cytoglobin's heme iron may exist either as a penta or hexacoordinated arrangement when exposed to different intracellular environments. Two cysteine residues at the surface of the protein form an intramolecular disulfide bond that regulates iron coordination, ligand binding, and peroxidase activity. Overall, biochemical results do not support a role for cytoglobin as a direct antioxidant enzyme that scavenges hydrogen peroxide because the rate of the reaction of cytoglobin with hydrogen peroxide is several orders of magnitude slower than metal and thiol-based peroxidases. Thus, alternative substrates such as fatty acids have been suggested and regulation of nitric oxide bioavailability through nitric oxide dioxygenase and nitrite reductase activities has received experimental support. Cytoglobin is broadly expressed in connective, muscle, and nervous tissues. Rational for differential cellular distribution is poorly understood but inducibility in response to hypoxia is one of the most established features of cytoglobin expression with regulation through the transcription factor hypoxia-inducible factor (HIF). Phenotypic characterization of cytoglobin deletion in the mouse have indicated broad changes that include a heightened inflammatory response and fibrosis, increase tumor burden, cardiovascular dysfunction, and hallmarks of senescence. Some of these changes might be reversed upon inhibition of nitric oxide synthase. However, subcellular and molecular interactions have been seldom characterized. In addition, specific molecular mechanisms of action are still lacking. We speculate that cytoglobin functionality will extend beyond nitric oxide handling and will have to encompass indirect regulatory antioxidant and redox sensing functions.
Collapse
Affiliation(s)
- Clinton Mathai
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Frances L Jourd'heuil
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | | | - David Jourd'heuil
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.
| |
Collapse
|
|
37
|
Gutiérrez-Camacho LR, Kormanovski A, Del Carmen Castillo-Hernández M, Guevara-Balcázar G, Lara-Padilla E. Alterations in glutathione, nitric oxide and 3-nitrotyrosine levels following exercise and/or hyperbaric oxygen treatment in mice with diet-induced diabetes. Biomed Rep 2020; 12:222-232. [PMID: 32257185 PMCID: PMC7100140 DOI: 10.3892/br.2020.1291] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 11/29/2019] [Indexed: 12/15/2022] Open
Abstract
Oxidative stress is involved in the development of diabetes. Nitric oxide (NO) contributes to oxidative stress, affects the synthesis of glutathione (GSH) in tissues and also regulates important physiological processes. The levels of nitrosative stress, assessed by measuring the levels of 3-nitrotirosina (3NT) as well as the bioavailability of NO are modulated by exercise and hyperbaric oxygenation (HBO). The aim of the present study was to evaluate the effects of exercise and HBO on the levels of NO, 3NT and GSH in tissues of various organs obtained from diabetic mice. Female mice were fed a high-fat/high-fructose diet to induce diabetes. Mice with diabetes were subjected to exercise and/or HBO. Initial and final concentrations of NO, 3NT and GSH were assessed in the muscle, liver, kidney, heart, spleen, lung, brain, visceral adipose, thoracic aorta and small intestine. Diabetes did not affect initial values of NO, although it significantly increased the levels of 3NT. The basal level of GSH in the diabetic group was lower than or comparable to that of the control group in the majority of the organs assessed. A negative correlation was observed between 3NT and GSH levels in the initial values of all tissues of the control group only, whereas all pathological tissues showed a positive correlation between NO and GSH. There was an increase or a stabilization of GSH levels in the majority of the organs in all treated mice despite the increase in nitrosative stress.
Collapse
Affiliation(s)
| | - Alexandre Kormanovski
- Instituto Politécnico Nacional, Escuela Superior de Medicina, Mexico City 11340, Mexico
| | | | | | - Eleazar Lara-Padilla
- Instituto Politécnico Nacional, Escuela Superior de Medicina, Mexico City 11340, Mexico
| |
Collapse
|
|
38
|
Vitturi DA, Maynard C, Olsufka M, Straub AC, Krehel N, Kudenchuk PJ, Nichol G, Sayre M, Kim F, Dezfulian C. Nitrite elicits divergent NO-dependent signaling that associates with outcome in out of hospital cardiac arrest. Redox Biol 2020; 32:101463. [PMID: 32087553 PMCID: PMC7033352 DOI: 10.1016/j.redox.2020.101463] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 02/01/2020] [Accepted: 02/11/2020] [Indexed: 01/16/2023] Open
Abstract
Brain and heart injury cause most out-of-hospital cardiac arrest deaths but limited pharmacotherapy exists to protect these tissues. Nitrite is a nitric oxide precursor that is protective in pre-clinical models of ischemic injury and safe in Phase I testing. Protection may occur by cGMP generation via the sGC pathway or through S-nitrosothiol and nitrated conjugated linoleic acid (NO2-CLA) formation. We hypothesized that nitrite provided during CPR signals through multiple pathways and that activation of signals is associated with OHCA outcome. To this end, we performed a secondary analysis of a phase 1 study of intravenous nitrite administration during resuscitation in adult out-of-hospital cardiac arrest. Associations between whole blood nitrite and derived plasma signals (cGMP and NO2-CLA) with patient characteristics and outcomes were defined using Chi-square or t-tests and multiple logistic regression. Whole blood nitrite levels correlated inversely with plasma NO2-CLA (p = 0.039) but not with cGMP. Patients with shockable rhythms had higher cGMP (p = 0.027), NO2-CLA (p < 0.0001) and trended towards lower nitrite (p = 0.077). Importantly, plasma cGMP and NO2-CLA levels were higher in survivors (p = 0.033 and 0.019) and in those with good neurological outcome (p = 0.046 and 0.021). Nitrite was lower in patients with good neurologic outcome (p = 0.029). cGMP (OR 4.02; 95% CI 1.04–15.54; p = 0.044) and NO2-CLA (OR 3.74; 95% CI 1.11–12.65; p = 0.034) were associated with survival. Nitrite (OR 0.20; 95% CI 0.05–0.08; p = 0.026) and NO2-CLA (OR 3.96; 95% CI 1.01–15.60; p = 0.049) were associated with favorable neurologic outcome. In summary, nitrite administration was associated with increased plasma cGMP and NO2-CLA formation in selected OHCA patients. Furthermore, patients with the highest levels of cGMP and NO2-CLA were more likely to survive and experience better neurological outcomes.
Collapse
Affiliation(s)
- Dario A Vitturi
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, USA; Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, USA
| | - Charles Maynard
- Department of Health Services, University of Washington, USA
| | - Michele Olsufka
- Department of Health Services, University of Washington, USA; Department of Medicine, Harborview Medical Center, University of Washington, USA
| | - Adam C Straub
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, USA; Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, USA
| | - Nick Krehel
- Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, USA
| | - Peter J Kudenchuk
- Department of Medicine, Harborview Medical Center, University of Washington, USA
| | - Graham Nichol
- Department of Medicine, Harborview Medical Center, University of Washington, USA
| | - Michael Sayre
- Department of Medicine, Harborview Medical Center, University of Washington, USA
| | - Francis Kim
- Department of Medicine, Harborview Medical Center, University of Washington, USA
| | - Cameron Dezfulian
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, USA; Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, USA.
| |
Collapse
|
|
39
|
Casin KM, Kohr MJ. An emerging perspective on sex differences: Intersecting S-nitrosothiol and aldehyde signaling in the heart. Redox Biol 2020; 31:101441. [PMID: 32007450 PMCID: PMC7212482 DOI: 10.1016/j.redox.2020.101441] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 01/20/2020] [Accepted: 01/22/2020] [Indexed: 12/17/2022] Open
Abstract
Cardiovascular disease is the leading cause of the death for both men and women. Although baseline heart physiology and the response to disease are known to differ by sex, little is known about sex differences in baseline molecular signaling, especially with regard to redox biology. In this review, we describe current research on sex differences in cardiac redox biology with a focus on the regulation of nitric oxide and aldehyde signaling. Furthermore, we argue for a new perspective on cardiovascular sex differences research, one that focuses on baseline redox biology without the elimination or disruption of sex hormones.
Collapse
Affiliation(s)
- Kevin M Casin
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
| | - Mark J Kohr
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
| |
Collapse
|
|
40
|
Kanipakam H, Sharma K, Thinlas T, Mohammad G, Pasha MAQ. Structural and functional alterations of nitric oxide synthase 3 due to missense variants associate with high-altitude pulmonary edema through dynamic study. J Biomol Struct Dyn 2020; 39:294-309. [PMID: 31902292 DOI: 10.1080/07391102.2019.1711190] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The human endothelial nitric oxide synthase (NOS3) is 28 Kbp at 7q36.1 and encodes protein comprising of 1280 amino acids. Being a major source of nitric oxide, the enzyme is crucial to the vascular homeostasis and thereby to be an important pharmaceutical target. We hence have been investigating this molecule in a high-altitude disorder namely, high-altitude pulmonary edema (HAPE). We performed a genome-wide association study (GWAS) in a case-control design of sojourners that included healthy controls and HAPE patients (n = 200) each. Four NOS3 missense SNPs i.e. rs1799983 (E298D), rs3918232 (V827M), rs3918201 (R885M) and rs3918234 (Q982L), were associated significantly with HAPE (P-value < 0.05). Furthermore, extensive in silico analyses were performed to predict the detrimental effect of the four variant types and their three most relevant co-factors namely, heme, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) that are accountable for amendment of protein stability leading to structural de-construction. Subsequently, we validated the findings in a larger sample size of the two study groups. HAPE patients had a higher frequency of the four variants and significantly decreased levels of circulating nitric oxide (NO) (P-value < 0.001). The in silico and human subjects findings complement each other. This study explored the impact of HAPE-associated NOS3 variants with its protein structure stability and holds promise to be current and future drug targets.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Hema Kanipakam
- Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi, India
| | - Kavita Sharma
- Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi, India
| | - Tashi Thinlas
- Department of Medicine, SNM Hospital, Leh, Ladakh, India
| | | | - M A Qadar Pasha
- Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi, India
| |
Collapse
|
|
41
|
Liu Y, Croft KD, Hodgson JM, Mori T, Ward NC. Mechanisms of the protective effects of nitrate and nitrite in cardiovascular and metabolic diseases. Nitric Oxide 2020; 96:35-43. [PMID: 31954804 DOI: 10.1016/j.niox.2020.01.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/18/2019] [Accepted: 01/13/2020] [Indexed: 12/28/2022]
Abstract
Within the body, NO is produced by nitric oxide synthases via converting l-arginine to citrulline. Additionally, NO is also produced via the NOS-independent nitrate-nitrite-NO pathway. Unlike the classical pathway, the nitrate-nitrite-NO pathway is oxygen independent and viewed as a back-up function to ensure NO generation during ischaemia/hypoxia. Dietary nitrate and nitrite have emerged as substrates for endogenous NO generation and other bioactive nitrogen oxides with promising protective effects on cardiovascular and metabolic function. In brief, inorganic nitrate and nitrite can decrease blood pressure, protect against ischaemia-reperfusion injury, enhance endothelial function, inhibit platelet aggregation, modulate mitochondrial function and improve features of the metabolic syndrome. However, many questions regarding the specific mechanisms of these protective effects on cardiovascular and metabolic diseases remain unclear. In this review, we focus on nitrate/nitrite bioactivation, as well as the potential mechanisms for nitrate/nitrite-mediated effects on cardiovascular and metabolic diseases. Understanding how dietary nitrate and nitrite induce beneficial effect on cardiovascular and metabolic diseases could open up novel therapeutic opportunities in clinical practice.
Collapse
Affiliation(s)
- Yang Liu
- School of Biomedical Sciences, University of Western Australia, Perth, Australia
| | - Kevin D Croft
- School of Biomedical Sciences, University of Western Australia, Perth, Australia
| | - Jonathan M Hodgson
- School of Biomedical Sciences, University of Western Australia, Perth, Australia; School of Medical and Health Sciences, Edith Cowan University, Perth, Australia
| | - Trevor Mori
- Medical School, University of Western Australia, Perth, Australia
| | - Natalie C Ward
- Medical School, University of Western Australia, Perth, Australia; School of Public Health and Curtin Health Innovation Research Institute, Curtin University, Perth, Australia.
| |
Collapse
|
|
42
|
Liu T, Mukosera GT, Blood AB. The role of gasotransmitters in neonatal physiology. Nitric Oxide 2019; 95:29-44. [PMID: 31870965 DOI: 10.1016/j.niox.2019.12.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 11/07/2019] [Accepted: 12/17/2019] [Indexed: 12/12/2022]
Abstract
The gasotransmitters, nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO), are endogenously-produced volatile molecules that perform signaling functions throughout the body. In biological tissues, these small, lipid-permeable molecules exist in free gaseous form for only seconds or less, and thus they are ideal for paracrine signaling that can be controlled rapidly by changes in their rates of production or consumption. In addition, tissue concentrations of the gasotransmitters are influenced by fluctuations in the level of O2 and reactive oxygen species (ROS). The normal transition from fetus to newborn involves a several-fold increase in tissue O2 tensions and ROS, and requires rapid morphological and functional adaptations to the extrauterine environment. This review summarizes the role of gasotransmitters as it pertains to newborn physiology. Particular focus is given to the vasculature, ventilatory, and gastrointestinal systems, each of which uniquely illustrate the function of gasotransmitters in the birth transition and newborn periods. Moreover, given the relative lack of studies on the role that gasotransmitters play in the newborn, particularly that of H2S and CO, important gaps in knowledge are highlighted throughout the review.
Collapse
Affiliation(s)
- Taiming Liu
- Department of Pediatrics, Division of Neonatology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
| | - George T Mukosera
- Department of Pediatrics, Division of Neonatology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
| | - Arlin B Blood
- Department of Pediatrics, Division of Neonatology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA; Lawrence D. Longo Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA.
| |
Collapse
|
|
43
|
Catalase-Like Antioxidant Activity is Unaltered in Hypochlorous Acid Oxidized Horse Heart Myoglobin. Antioxidants (Basel) 2019; 8:antiox8090414. [PMID: 31540488 PMCID: PMC6770884 DOI: 10.3390/antiox8090414] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/27/2019] [Accepted: 09/16/2019] [Indexed: 01/01/2023] Open
Abstract
Activated neutrophils release myeloperoxidase that produces the potent oxidant hypochlorous acid (HOCl). Exposure of the oxygen transport protein horse heart myoglobin (hhMb) to HOCl inhibits Iron III (Fe(III))-heme reduction by cytochrome b5 to oxygen-binding Iron II (Fe(II))Mb. Pathological concentrations of HOCl yielded myoglobin oxidation products of increased electrophoretic mobility and markedly different UV/Vis absorbance. Mass analysis indicated HOCl caused successive mass increases of 16 a.m.u., consistent serial addition of molecular oxygen to the protein. By contrast, parallel analysis of protein chlorination by quantitative mass spectrometry revealed a comparatively minor increase in the 3-chlorotyrosine/tyrosine ratio. Pre-treatment of hhMb with HOCl affected the peroxidase reaction between the hemoprotein and H2O2 as judged by a HOCl dose-dependent decrease in spin-trapped tyrosyl radical detected by electron paramagnetic resonance (EPR) spectroscopy and the rate constant of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS) oxidation. By contrast, Mb catalase-like antioxidant activity remained unchanged under the same conditions. Notably, HOCl-modification of Mb decreased the rate of ferric-to-ferrous Mb reduction by a cytochrome b5 reductase system. Taken together, these data indicate oxidizing HOCl promotes Mb oxidation but not chlorination and that oxidized Mb shows altered Mb peroxidase-like activity and diminished rates of one-electron reduction by cytochrome b5 reductase, possibly affecting oxygen storage and transport however, Mb-catalase-like antioxidant activity remains unchanged.
Collapse
|
|
44
|
Mincu RI, Mahabadi AA, Michel L, Mrotzek SM, Schadendorf D, Rassaf T, Totzeck M. Cardiovascular Adverse Events Associated With BRAF and MEK Inhibitors: A Systematic Review and Meta-analysis. JAMA Netw Open 2019; 2:e198890. [PMID: 31397860 PMCID: PMC6692687 DOI: 10.1001/jamanetworkopen.2019.8890] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
IMPORTANCE Cardiovascular adverse events (CVAEs) after treatment with BRAF and MEK inhibitors in patients with melanoma remain incompletely characterized. OBJECTIVE To determine the association of BRAF and MEK inhibitor treatment with CVAEs in patients with melanoma compared with BRAF inhibitor monotherapy. DATA SOURCES PubMed, Cochrane, and Web of Science were systematically searched for keywords vemurafenib, dabrafenib, encorafenib, trametinib, binimetinib, and cobinimetinib from database inception through November 30, 2018. STUDY SELECTION Randomized clinical trials reporting on CVAEs in patients with melanoma being treated with BRAF and MEK inhibitors compared with patients with melanoma being treated with BRAF inhibitor monotherapy were selected. DATA EXTRACTION AND SYNTHESIS Data assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Pooled relative risks (RRs) and 95% CIs were determined using random-effects and fixed-effects analyses. Subgroup analyses were conducted to assess study-level characteristics associated with CVAEs. MAIN OUTCOMES AND MEASURES The selected end points were pulmonary embolism, a decrease in left ventricular ejection fraction, arterial hypertension, myocardial infarction, atrial fibrillation, and QTc interval prolongation. All-grade and high-grade (≥3) CVAEs were recorded. RESULTS Overall, 5 randomized clinical trials including 2317 patients with melanoma were selected. Treatment with BRAF and MEK inhibitors was associated with an increased risk of pulmonary embolism (RR, 4.36; 95% CI, 1.23-15.44; P = .02), a decrease in left ventricular ejection fraction (RR, 3.72; 95% CI, 1.74-7.94; P < .001), and arterial hypertension (RR, 1.49; 95% CI, 1.12-1.97; P = .005) compared with BRAF inhibitor monotherapy. The RRs for myocardial infarction, atrial fibrillation, and QTc prolongation were similar between the groups. These results were consistent when assessing high-grade CVAEs (left ventricular ejection fraction: RR, 2.79; 95% CI, 1.36-5.73; P = .005; I2 = 29%; high-grade arterial hypertension: RR, 1.54; 95% CI, 1.14-2.08; P = .005; I2 = 0%), but RRs for high-grade pulmonary embolism were similar between groups. A higher risk of a decrease in left ventricular ejection fraction was associated with patients with a mean age younger than 55 years (RR, 26.50; 95% CI, 3.58-196.10; P = .001), and the associated risk of pulmonary embolism was higher for patients with a mean follow-up time longer than 15 months (RR, 7.70; 95% CI, 1.40-42.12; P = .02). CONCLUSIONS AND RELEVANCE Therapy with BRAF and MEK inhibitors was associated with a higher risk of CVAEs compared with BRAF inhibitor monotherapy. The findings may help to balance between beneficial melanoma treatment and cardiovascular morbidity and mortality.
Collapse
Affiliation(s)
- Raluca I. Mincu
- West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, University Hospital Essen, Essen, Germany
| | - Amir A. Mahabadi
- West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, University Hospital Essen, Essen, Germany
| | - Lars Michel
- West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, University Hospital Essen, Essen, Germany
| | - Simone M. Mrotzek
- West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, University Hospital Essen, Essen, Germany
| | - Dirk Schadendorf
- West German Cancer Center, Department of Dermatology, University Hospital Essen, Essen, Germany
| | - Tienush Rassaf
- West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, University Hospital Essen, Essen, Germany
| | - Matthias Totzeck
- West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, University Hospital Essen, Essen, Germany
| |
Collapse
|
|
45
|
Reciprocal regulation of sulfite oxidation and nitrite reduction by mitochondrial sulfite oxidase. Nitric Oxide 2019; 89:22-31. [PMID: 31002874 DOI: 10.1016/j.niox.2019.04.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/08/2019] [Accepted: 04/11/2019] [Indexed: 01/08/2023]
Abstract
The oxygen-independent nitrate-nitrite-nitric oxide (NO) pathway is considered as a substantial source of NO in mammals. Dietary nitrate/nitrite are distributed throughout the body and reduced to NO by the action of various enzymes. The intermembrane spaced (IMS), molybdenum cofactor-dependent sulfite oxidase (SO) was shown to catalyze such a nitrite reduction. In this study we asked whether the primary function of SO - sulfite oxidation - and its novel function - nitrite reduction - impact each other. First, we utilized benzyl viologen as artificial electron donor to investigate steady state NO synthesis by SO and found fast (kcat = 14 s-1) nitrite reduction of SO full-length and its isolated molybdenum domain at pH 6.5. Next, we determined the impact of nitrite on pre-steady state kinetics in SO catalysis and identified nitrite as a pH-dependent inhibitor of SO reductive and oxidative half reaction. Finally, we report on the time-dependent formation of the paramagnetic Mo(V) species following nitrite reduction and demonstrate that sulfite inhibits nitrite reduction. In conclusion, we propose a pH-dependent reciprocal regulation of sulfite oxidation and nitrite reduction by each substrate, thus facilitating quick responses to hypoxia induced changes in the IMS, which may function in protecting the cell from reactive oxygen species production.
Collapse
|
|
46
|
Park JW, Piknova B, Dey S, Noguchi CT, Schechter AN. Compensatory mechanisms in myoglobin deficient mice preserve NO homeostasis. Nitric Oxide 2019; 90:10-14. [PMID: 31173908 DOI: 10.1016/j.niox.2019.06.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/31/2019] [Accepted: 06/02/2019] [Indexed: 12/12/2022]
Abstract
The mechanism for nitric oxide (NO) generation from reduction of nitrate (NO3-) and nitrite (NO2-) has gained increasing attention due to the potential beneficial effects of NO in cardiovascular diseases and exercise performance. We have previously shown in rodents that skeletal muscle is the major nitrate reservoir in the body and that exercise enhances the nitrate reduction pathway in the muscle tissue and have proposed that nitrate in muscle originates from diet, the futile cycle of nitric oxide synthase 1 (NOS1) and/or oxidation of NO by oxymyoglobin. In the present study, we tested the hypothesis that lack of myoglobin expression would decrease nitrate levels in skeletal muscle. We observed a modest but significant decrease of nitrate level in skeletal muscle of myoglobin deficient mice compared to littermate control mice (17.3 vs 12.8 nmol/g). In contrast, a NOS inhibitor, L-NAME or a low nitrite/nitrate diet treatment led to more pronounced decreases of nitrate levels in the skeletal muscle of both control and myoglobin deficient mice. Nitrite levels in the skeletal muscle of both types of mice were similar (0.48 vs 0.42 nmol/g). We also analyzed the expression of several proteins that are closely related to NO metabolism to examine the mechanism by which nitrate and nitrite levels are preserved in the absence of myoglobin. Western blot analyses suggest that the protein levels of xanthine oxidoreductase and sialin, a nitrate transporter, both increased in the skeletal muscle of myoglobin deficient mice. These results are compatible with our previously reported model of nitrate production in muscle and suggest that myoglobin deficiency activates compensatory mechanisms to sustain NO homeostasis.
Collapse
Affiliation(s)
- Ji Won Park
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Barbora Piknova
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Soumyadeep Dey
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Constance T Noguchi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Alan N Schechter
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
| |
Collapse
|
|
47
|
del Campo L, Sánchez‐López A, Salaices M, von Kleeck RA, Expósito E, González‐Gómez C, Cussó L, Guzmán‐Martínez G, Ruiz‐Cabello J, Desco M, Assoian RK, Briones AM, Andrés V. Vascular smooth muscle cell-specific progerin expression in a mouse model of Hutchinson-Gilford progeria syndrome promotes arterial stiffness: Therapeutic effect of dietary nitrite. Aging Cell 2019; 18:e12936. [PMID: 30884114 PMCID: PMC6516150 DOI: 10.1111/acel.12936] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 01/23/2019] [Accepted: 02/03/2019] [Indexed: 12/11/2022] Open
Abstract
Vascular stiffness is a major cause of cardiovascular disease during normal aging and in Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder caused by ubiquitous progerin expression. This mutant form of lamin A causes premature aging associated with cardiovascular alterations that lead to death at an average age of 14.6 years. We investigated the mechanisms underlying vessel stiffness in LmnaG609G/G609G mice with ubiquitous progerin expression, and tested the effect of treatment with nitrites. We also bred LmnaLCS/LCS Tie2Cre+/tg and LmnaLCS/LCS SM22αCre+/tg mice, which express progerin specifically in endothelial cells (ECs) and in vascular smooth muscle cells (VSMCs), respectively, to determine the specific contribution of each cell type to vascular pathology. We found vessel stiffness and inward remodeling in arteries of LmnaG609G/G609G and LmnaLCS/LCS SM22αCre+/tg , but not in those from LmnaLCS/LCS Tie2Cre+/tg mice. Structural alterations in aortas of progeroid mice were associated with decreased smooth muscle tissue content, increased collagen deposition, and decreased transverse waving of elastin layers in the media. Functional studies identified collagen (unlike elastin and the cytoskeleton) as an underlying cause of aortic stiffness in progeroid mice. Consistent with this, we found increased deposition of collagens III, IV, V, and XII in the media of progeroid aortas. Vessel stiffness and inward remodeling in progeroid mice were prevented by adding sodium nitrite in drinking water. In conclusion, LmnaG609G/G609G arteries exhibit stiffness and inward remodeling, mainly due to progerin-induced damage to VSMCs, which causes increased deposition of medial collagen and a secondary alteration in elastin structure. Treatment with nitrites prevents vascular stiffness in progeria.
Collapse
Affiliation(s)
- Lara del Campo
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
| | - Amanda Sánchez‐López
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
| | - Mercedes Salaices
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
- Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto de Investigación Hospital La Paz (IdiPaz)Universidad Autónoma de MadridMadridSpain
| | - Ryan A. von Kleeck
- Center for Engineering Mechanobiology and Department of Systems Pharmacology and Translational TherapeuticsUniversity of PennsylvaniaPhiladelphiaPennsylvania
| | - Elba Expósito
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
| | - Cristina González‐Gómez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
| | - Lorena Cussó
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- Departamento de Bioingeniería e Ingeniería AeroespacialUniversidad Carlos III de MadridMadridSpain
- Instituto de Investigación Sanitaria Gregorio MarañónMadridSpain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)Spain
| | - Gabriela Guzmán‐Martínez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- Cardiac Imaging Unit, Cardiology DepartmentHospital Universitario La PazMadridSpain
| | - Jesús Ruiz‐Cabello
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- CIBER de Enfermedades Respiratorias (CIBERES)Spain
- Present address:
CIC biomaGUNE and Ikerbasque Basque Foundation for ScienceSan SebastiánSpain
- Present address:
Universidad Complutense MadridMadridSpain
| | - Manuel Desco
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- Departamento de Bioingeniería e Ingeniería AeroespacialUniversidad Carlos III de MadridMadridSpain
- Instituto de Investigación Sanitaria Gregorio MarañónMadridSpain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)Spain
| | - Richard K. Assoian
- Center for Engineering Mechanobiology and Department of Systems Pharmacology and Translational TherapeuticsUniversity of PennsylvaniaPhiladelphiaPennsylvania
| | - Ana M. Briones
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
- Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto de Investigación Hospital La Paz (IdiPaz)Universidad Autónoma de MadridMadridSpain
| | - Vicente Andrés
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
| |
Collapse
|
|
48
|
Jung H, Choi EK, Baek SI, Cho C, Jin Y, Kwak KH, Jeon Y, Park SS, Kim S, Lim DG. The Effect of Nitric Oxide on Remote Ischemic Preconditioning in Renal Ischemia Reperfusion Injury in Rats. Dose Response 2019; 17:1559325819853651. [PMID: 31191188 PMCID: PMC6542129 DOI: 10.1177/1559325819853651] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 04/29/2019] [Accepted: 04/30/2019] [Indexed: 12/12/2022] Open
Abstract
Although remote ischemic preconditioning (RIPC) is an organ-protective maneuver from subsequent ischemia reperfusion injury (IRI) by application of brief ischemia and reperfusion to other organs, its mechanism remains unclear. However, it is known that RIPC reduces the heart, brain, and liver IRI, and that nitric oxide (NO) is involved in the mechanism of this effect. To identify the role of NO in the protective effect of RIPC in renal IRI, this study examined renal function, oxidative status, and histopathological changes using N-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor. Remote ischemic preconditioning was produced by 3 cycles of 5 minutes ischemia and 5 minutes reperfusion. Blood urea nitrogen, creatinine (Cr), and renal tissue malondialdehyde levels were lower, histopathological damage was less severe, and superoxide dismutase level was higher in the RIPC + IRI group than in the IRI group. The renoprotective effect was reversed by L-NAME. Obtained results suggest that RIPC before renal IRI contributes to improvement of renal function, increases antioxidative marker levels, and decreases oxidative stress marker levels and histopathological damage. Moreover, NO is likely to play an important role in this protective effect of RIPC on renal IRI.
Collapse
Affiliation(s)
- Hoon Jung
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Eun Kyung Choi
- Department of Anesthesiology and Pain Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Seung Ik Baek
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Changhee Cho
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Yehun Jin
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Kyung Hwa Kwak
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Younghoon Jeon
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Sung-Sik Park
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Sioh Kim
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Dong Gun Lim
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| |
Collapse
|
|
49
|
Amdahl MB, DeMartino AW, Tejero J, Gladwin MT. Cytoglobin at the Crossroads of Vascular Remodeling. Arterioscler Thromb Vasc Biol 2019; 37:1803-1805. [PMID: 28954806 DOI: 10.1161/atvbaha.117.310058] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Matthew B Amdahl
- From the Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine (M.B.A., A.W.D., J.T., M.T.G.), Department of Bioengineering (M.B.A.), and Division of Pulmonary, Allergy, and Critical Care Medicine (A.W.D., J.T., M.T.G.), University of Pittsburgh, PA
| | - Anthony W DeMartino
- From the Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine (M.B.A., A.W.D., J.T., M.T.G.), Department of Bioengineering (M.B.A.), and Division of Pulmonary, Allergy, and Critical Care Medicine (A.W.D., J.T., M.T.G.), University of Pittsburgh, PA
| | - Jesús Tejero
- From the Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine (M.B.A., A.W.D., J.T., M.T.G.), Department of Bioengineering (M.B.A.), and Division of Pulmonary, Allergy, and Critical Care Medicine (A.W.D., J.T., M.T.G.), University of Pittsburgh, PA
| | - Mark T Gladwin
- From the Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine (M.B.A., A.W.D., J.T., M.T.G.), Department of Bioengineering (M.B.A.), and Division of Pulmonary, Allergy, and Critical Care Medicine (A.W.D., J.T., M.T.G.), University of Pittsburgh, PA.
| |
Collapse
|
|
50
|
Abstract
OBJECTIVE This research was aimed to investigate the correct dose of nitrite that would act as a protection against the ischemic effects induced by acute myocardial infarction (AMI). METHODS Mice were randomly divided into a sham-operation group (sham), an AMI operation group (AMI), and a nitrite pretreatment+AMI operation group (N+AMI). Seven days before the AMI operation, mice in the N+AMI group were pretreated with sodium nitrite in drinking water. RESULTS One week after the AMI operation, serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities in both AMI and N+AMI group were significantly higher than those in the sham group, but there were no significant differences between AMI and N+AMI mice. Contents of inducible nitric oxide synthase (iNOS) in the noninfarct area of the left ventricle in the N+AMI mice were significantly higher than those in the AMI mice, with no difference in the infarct area. Coagulation necrosis in the cardiomyocytes was observed in both AMI and N+AMI mice; however, it was less severe in the N+AMI mice. Western blot analyses showed that nitrite pretreatment resulted in up-regulation of antiapoptotic factors Bcl-2 and p21waf1/cip1 signal proteins, but down-regulation of the proapoptotic factor Bax signal protein. Furthermore, nitrite pretreatment also showed significant alleviation of AMI-induced signal protein expressions of inflammatory factors of NF-K B and oxidative factors of Hsp 70 and HO-1. CONCLUSION These results suggest that nitrite show certain protective effects against the ischemic effects induced by AMI in mice, which might be attributed to the synthesis of NO induced by iNOS through up-regulation of antiapoptotic factors and down-regulation of proapoptotic and inflammatory factors.
Collapse
|