Endothelial alpha globin is a nitrite reductase

AbstractSmall artery vasodilation in response to hypoxia is essential for matching oxygen supply to tissue oxygen demand. One source of hypoxic dilation via nitric oxide (NO) signaling is nitrite reduction by erythrocytic hemoglobin (α2β2). However, the alpha subunit of hemoglobin is also expressed in resistance artery endothelium and localized to myoendothelial junctions, a subcellular domain that contacts underlying vascular smooth muscle cells. We hypothesized that nitrite reduction mediated by endothelial alpha globin may occur at myoendothelial junctions to regulate hypoxic vasodilation. To test this concept, we created two novel mouse strains: one lacking alpha globin specifically in endothelium (EC Hba1Δ/Δ) and one where alpha globin is mutated such that its inhibitory association with endothelial NO synthase (eNOS) is prevented (Hba1WT/Δ36-39). In EC Hba1Δ/Δ or Hba1WT/Δ36-39 mice hemoglobin levels, hematocrit and erythrocyte counts were unchanged from littermate controls. Loss of the full alpha globin protein from the endothelium in the EC Hba1Δ/Δ model was associated with decreased exercise capacity and decreased intracellular nitrite utilization in hypoxic conditions. These effects were not seen in Hba1WT/Δ36-39 animals. Hypoxia induced vasodilation was decreased by 60% in isolated thoracodorsal arteries from EC Hba1Δ/Δ, while infusion of erythrocytes only partially rescued the dilatory response. Lastly, unlike other models where blood pressure is decreased, EC Hba1Δ/Δ blood pressure was not altered in response to hypoxia. Overall, we conclude that alpha globin in the resistance artery endothelium can act as a nitrite reductase to provide a local vasodilatory response to hypoxia.

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Electron Paramagnetic Resonance Investigation of Nitrite Binding in Myoglobin

10.1101/252775 ◽

2018 ◽

Author(s):

Matthew Bawn ◽

Fraser MacMillan

Keyword(s):

Electron Paramagnetic Resonance ◽

High Spin ◽

Nitrite Reductase ◽

Binding Mode ◽

Nitrite Reduction ◽

Paramagnetic Resonance ◽

High Ph ◽

Hypoxic Conditions ◽

Electron Paramagnetic ◽

Iron Center

ABSTRACTIt has been proposed that myoglobin (Mb) may act as a nitrite reductase under hypoxic conditions. Any mechanism describing such activity should take into account the binding geometry of the ligand to the heme. Crystal structures of horse-heart Mb and human hemoglobin-nitrite complexes suggest that the anion adopts an uncommon O-nitrito binding mode. Electron Paramagnetic Resonance (EPR) spectroscopy was employed to investigate the nature of nitrite binding to Mb at pH values ranging from 6.5 to 10.8. Results suggest that for ferric Mb at low pH, nitrite binds in the O-bound nitrito mode resulting in a low-spin (LS) iron center. Further a high-spin (HS) iron center is observed at high pH in Mb-Nitrite with spectral values different to that of purely HS-Mb that is proposed to be due to an N-bound nitrite. The yields of these two species were found to be influenced by pH.BackgroundMyoglobin has been theorized to have a role as a nitrite reductase.ResultsO-bound nitrite produces a low-spin ferric heme complex, whilst at high pH a high-spin species is found proposed to be the N-bound form.ConclusionNitrite may bind to heme in myoglobin via N-nitro or O-nitrito mode.SignificanceThe mechanism of any nitrite reduction will depend on its binding to the heme cofactor.

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HEART COMPLICATIONS IN HYPERTHYROIDISM

Journal of Medicine and Pharmacy ◽

10.34071/jmp.2011.2.1 ◽

2011 ◽

pp. 7-17

Author(s):

Hai Thuy Nguyen ◽

Anh Vu Nguyen

Keyword(s):

Atrial Fibrillation ◽

Blood Pressure ◽

Heart Rate ◽

Heart Diseases ◽

Systolic Dysfunction ◽

Oxygen Demand ◽

Left Ventricular ◽

Cardiac Contraction ◽

Cardiac Complications ◽

Cardiac Symptoms

Thyroid hormone increases the force of the contraction and the amount of the heart muscle oxygen demand. It also increases the heart rate. Due to these reasons, the work of the heart is greatly increased in hyperthyroidism. Hyperthyroidism increases the amount of nitric oxide in the intima, lead them to be dilated and become less stiff. Cardiac symptoms can be seen in anybody with hyperthyroidism, but can be particularly dangerous in whom have underlying heart diseases. Common symptoms include: tachycardia and palpitations. Occult hyperthyroidism is a common cause of an increased heart rate at rest and with mild exertion. Hyperthyroidism can also produce a host of other arrhythmias such as PVCs, ventricular tachycardia and especially atrial fibrillation. Left ventricular diastolic dysfunction and systolic dysfunction, Mitral regurgitation and mitral valve prolapsed are heart complications of hyperthyroism could be detected by echocardiography. The forceful cardiac contraction increases the systolic blood pressure despite the increased relaxation in the blood vessels reduces the diastolic blood pressure. Atrial fibrillation, atrial enlargement and congestive heart failure are important cardiac complications of hyperthyroidism. An increased risks of stroke is common in patients with atrial fibrillation. Graves disease is linked to autoimmune complications, such as cardiac valve involvement, pulmonary arterial hypertension and specific cardiomyopathy. Worsening angina: Patients with coronary artery disease often experience a marked worsening in symptoms with hyperthyroidism. These can include an increase in chest pain (angina) or even a heart attack.

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Increased nitrite reductase activity of fetal versus adult ovine hemoglobin

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00601.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. H237-H246 ◽

Cited By ~ 21

Author(s):

Arlin B. Blood ◽

Mauro Tiso ◽

Shilpa T. Verma ◽

Jennifer Lo ◽

Mahesh S. Joshi ◽

...

Keyword(s):

Nitrite Reductase ◽

Chronic Hypoxia ◽

Reductase Activity ◽

Fetal Hemoglobin ◽

Nitrite Reduction ◽

No Production ◽

Low Oxygen ◽

Nitrite Reductase Activity ◽

Adult Hemoglobin ◽

Severe Ischemia

Growing evidence indicates that nitrite, NO2−, serves as a circulating reservoir of nitric oxide (NO) bioactivity that is activated during physiological and pathological hypoxia. One of the intravascular mechanisms for nitrite conversion to NO is a chemical nitrite reductase activity of deoxyhemoglobin. The rate of NO production from this reaction is increased when hemoglobin is in the R conformation. Because the mammalian fetus exists in a low-oxygen environment compared with the adult and is exposed to episodes of severe ischemia during the normal birthing process, and because fetal hemoglobin assumes the R conformation more readily than adult hemoglobin, we hypothesized that nitrite reduction to NO may be enhanced in the fetal circulation. We found that the reaction was faster for fetal than maternal hemoglobin or blood and that the reactions were fastest at 50–80% oxygen saturation, consistent with an R-state catalysis that is predominant for fetal hemoglobin. Nitrite concentrations were similar in blood taken from chronically instrumented normoxic ewes and their fetuses but were elevated in response to chronic hypoxia. The findings suggest an augmented nitrite reductase activity of fetal hemoglobin and that the production of nitrite may participate in the regulation of vascular NO homeostasis in the fetus.

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Why Orange Guaymas Basin Beggiatoa spp. Are Orange: Single-Filament-Genome-Enabled Identification of an Abundant Octaheme Cytochrome with Hydroxylamine Oxidase, Hydrazine Oxidase, and Nitrite Reductase Activities

Applied and Environmental Microbiology ◽

10.1128/aem.02538-12 ◽

2012 ◽

Vol 79 (4) ◽

pp. 1183-1190 ◽

Cited By ~ 27

Author(s):

Barbara J. MacGregor ◽

Jennifer F. Biddle ◽

Jason R. Siebert ◽

Eric Staunton ◽

Eric L. Hegg ◽

...

Keyword(s):

Nitrite Reductase ◽

Pure Culture ◽

Gulf Of California ◽

Microbial Mats ◽

Physiological Role ◽

Nitrite Reduction ◽

Cold Seeps ◽

Single Filament ◽

Guaymas Basin ◽

Content Type

ABSTRACTOrange, white, and yellow vacuolatedBeggiatoaceaefilaments are visually dominant members of microbial mats found near sea floor hydrothermal vents and cold seeps, with orange filaments typically concentrated toward the mat centers. No marine vacuolateBeggiatoaceaeare yet in pure culture, but evidence to date suggests they are nitrate-reducing, sulfide-oxidizing bacteria. The nearly complete genome sequence of a single orangeBeggiatoa(“CandidatusMaribeggiatoa”) filament from a microbial mat sample collected in 2008 at a hydrothermal site in Guaymas Basin (Gulf of California, Mexico) was recently obtained. From this sequence, the gene encoding an abundant soluble orange-pigmented protein in Guaymas Basin mat samples (collected in 2009) was identified by microcapillary reverse-phase high-performance liquid chromatography (HPLC) nano-electrospray tandem mass spectrometry (μLC–MS-MS) of a pigmented band excised from a denaturing polyacrylamide gel. The predicted protein sequence is related to a large group of octaheme cytochromes whose few characterized representatives are hydroxylamine or hydrazine oxidases. The protein was partially purified and shown byin vitroassays to have hydroxylamine oxidase, hydrazine oxidase, and nitrite reductase activities. From what is known ofBeggiatoaceaephysiology, nitrite reduction is the most likelyin vivorole of the octaheme protein, but future experiments are required to confirm this tentative conclusion. Thus, while present-day genomic and proteomic techniques have allowed precise identification of an abundant mat protein, and its potential activities could be assayed, proof of its physiological role remains elusive in the absence of a pure culture that can be genetically manipulated.

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Abstract P218: The Association Of Mid-life Cumulative Exposure To Systolic Blood Pressure, Myocardial Oxygen Demand, And Hypertension With Later-life Central Arterial Stiffness And Its 5-year Change: The Atherosclerosis Risk In Communities Study - Neurocognitive Study (ARIC-NCS)

Circulation ◽

10.1161/circ.143.suppl_1.p218 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Michelle L Meyer ◽

Veeral Saraiya ◽

Hirofumi Tanaka ◽

Priya Palta ◽

Timothy M Hughes ◽

...

Keyword(s):

Blood Pressure ◽

Arterial Stiffness ◽

Systolic Blood Pressure ◽

Oxygen Demand ◽

Later Life ◽

Cumulative Exposure ◽

Rate Pressure Product ◽

Myocardial Oxygen Demand ◽

Small Magnitude ◽

Cumulative Exposures

Background: Greater central artery stiffness predicts cardiovascular disease and all-cause mortality, thus understanding arterial stiffness determinants has prevention implications. Reports of the temporal association of blood pressure with arterial stiffness are conflicting and the association with myocardial oxygen demand has not been evaluated. Objective: Characterize the association of mid- to later-life cumulative exposure to systolic blood pressure (SBP), myocardial oxygen demand, and hypertension (HTN) with arterial stiffness and its 5-year change in older adults. Methods: We included 1,975 adults (1151 women; 359 Black; visit 5 mean age 74 years) examined in visits 5 (2011-13) and 6 or 7 (2016-19) of the population-based ARIC-NCS with measures of arterial stiffness (carotid-femoral pulse wave velocity (cfPWV)). Higher cfPWV indicates greater arterial stiffness. We calculated cumulative exposures as the sum of averages from four consecutive visits from 1987-89 to 1996-98 divided by total time. Myocardial oxygen demand was calculated as the rate pressure product (RPP): (SBP x heart rate)/1,000. We derived HTN duration as the time since first HTN detection. Associations of cumulative exposures with visit 5 cfPWV and the 5-year cfPWV change were evaluated by multivariable linear regression adjusted for demographics and cardiometabolic factors. Results: Over the mean 5.7 years between visits 5 and 6 or 7, cfPWV increased by 144.9 cm/s (SD: 276.0; range -680.0, 961.5 cm/s). HTN at any visit, duration, and the time-weighted cumulative measures were associated with higher visit 5 cfPWV (Table). Prevalent HTN was inversely associated with cfPWV change. No statistically significant associations were observed for the other exposures and cfPWV change. Conclusion: Cumulative exposure to SBP, RPP, and HTN are modifiable traits associated with higher cfPWV at later-life, but not with rate of cfPWV change in older adulthood. HTN at visit 5 was associated with lower cfPWV change, albeit the change is of small magnitude.

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Erbb is linked to the alpha-globin locus on mouse chromosome 11.

Molecular and Cellular Biology ◽

10.1128/mcb.5.7.1784 ◽

1985 ◽

Vol 5 (7) ◽

pp. 1784-1786 ◽

Cited By ~ 18

Author(s):

J Silver ◽

J B Whitney ◽

C Kozak ◽

G Hollis ◽

I Kirsch

Keyword(s):

Mouse Chromosome ◽

Human Gene ◽

Congenic Mouse ◽

Mouse Strains ◽

Somatic Cell Hybrids ◽

Chromosome 11 ◽

Homologous Sequences ◽

Alpha Globin ◽

Mouse Chromosome 11 ◽

Congenic Mouse Strains

A fragment of the human gene for c-erb-B was used to map homologous sequences in mice. Analysis of somatic cell hybrids and recombinant inbred and congenic mouse strains indicated that this gene, designated Erbb, is closely linked to the gene for alpha-globin on mouse chromosome 11. Several genes controlling hematopoietic differentiation map to mouse chromosome 11.

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IMMEDIATE HEMODYNAMIC EFFECTS OF ISOPROTERENOL

Canadian Journal of Biochemistry and Physiology ◽

10.1139/y63-221 ◽

1963 ◽

Vol 41 (1) ◽

pp. 1949-1953 ◽

Cited By ~ 1

Author(s):

Margaret Beznák ◽

P. Hacker

Keyword(s):

Blood Pressure ◽

Cardiac Output ◽

Oxygen Consumption ◽

Subcutaneous Injection ◽

Direct Action ◽

Peripheral Resistance ◽

Oxygen Demand ◽

Hemodynamic Effects ◽

Hemodynamic Changes ◽

Histological Damage

Subcutaneous injection of 40 mg/kg isoproterenol is followed within 2 minutes by a fall in blood pressure and peripheral resistance, by tachycardia, and by an increase in cardiac output. It seems likely that these hemodynamic changes are a consequence of a direct action of isoproterenol on the myocardium. Isoproterenol also causes a significant increase in the oxygen consumption of the rats. The increased oxygen demand of the tissues may play a role in maintaining the hemodynamic changes for periods of more than an hour after isoproterenol. Signs of histological damage in the myocardium begin to appear without affecting the function of the cardiovascular system, as measured by the tests used.

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New insights into the activity of Pseudomonas aeruginosa cd1 nitrite reductase

Biochemical Society Transactions ◽

10.1042/bst0361155 ◽

2008 ◽

Vol 36 (6) ◽

pp. 1155-1159 ◽

Cited By ~ 14

Author(s):

Serena Rinaldo ◽

Alessandro Arcovito ◽

Giorgio Giardina ◽

Nicoletta Castiglione ◽

Maurizio Brunori ◽

...

Keyword(s):

Nitric Oxide ◽

Pseudomonas Aeruginosa ◽

Nitrite Reductase ◽

Nitrite Reduction ◽

Nitrite Reductases ◽

Cytochrome Cd1 ◽

Haem Iron ◽

Shed Light ◽

Denitrification Process

The cytochrome cd1 nitrite reductases are enzymes that catalyse the reduction of nitrite to nitric oxide (NO) in the bacterial energy conversion denitrification process. These enzymes contain two different redox centres: one covalently bound c-haem, which is reduced by external donors, and one peculiar d1-haem, where catalysis occurs. In the present paper, we summarize the current understanding of the reaction of nitrite reduction in the light of the most recent results on the enzyme from Pseudomonas aeruginosa and discuss the differences between enzymes from different organisms. We have evidence that release of NO from the ferrous d1-haem occurs rapidly enough to be fully compatible with the turnover, in contrast with previous hypotheses, and that the substrate nitrite is able to displace NO from the d1-haem iron. These results shed light on the mechanistic details of the activity of cd1 nitrite reductases and on the biological role of the d1-haem, whose presence in this class of enzymes has to date been unexplained.

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The functional nitrite reductase activity of the heme-globins

Blood ◽

10.1182/blood-2008-01-115261 ◽

2008 ◽

Vol 112 (7) ◽

pp. 2636-2647 ◽

Cited By ~ 184

Author(s):

Mark T. Gladwin ◽

Daniel B. Kim-Shapiro

Keyword(s):

Small Molecules ◽

Nitrite Reductase ◽

Reductase Activity ◽

Vital Role ◽

Nitrite Reduction ◽

Cellular Respiration ◽

Oxygen Binding ◽

Nitrite Reductase Activity ◽

Hypoxic Vasodilation ◽

Anaerobic Conversion

AbstractHemoglobin and myoglobin are among the most extensively studied proteins, and nitrite is one of the most studied small molecules. Recently, multiple physiologic studies have surprisingly revealed that nitrite represents a biologic reservoir of NO that can regulate hypoxic vasodilation, cellular respiration, and signaling. These studies suggest a vital role for deoxyhemoglobin- and deoxymyoglobin-dependent nitrite reduction. Biophysical and chemical analysis of the nitrite-deoxyhemoglobin reaction has revealed unexpected chemistries between nitrite and deoxyhemoglobin that may contribute to and facilitate hypoxic NO generation and signaling. The first is that hemoglobin is an allosterically regulated nitrite reductase, such that oxygen binding increases the rate of nitrite conversion to NO, a process termed R-state catalysis. The second chemical property is oxidative denitrosylation, a process by which the NO formed in the deoxyhemoglobin-nitrite reaction that binds to other deoxyhemes can be released due to heme oxidation, releasing free NO. Third, the reaction undergoes a nitrite reductase/anhydrase redox cycle that catalyzes the anaerobic conversion of 2 molecules of nitrite into dinitrogen trioxide (N2O3), an uncharged molecule that may be exported from the erythrocyte. We will review these reactions in the biologic framework of hypoxic signaling in blood and the heart.

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Abstract 15839: Effect of Serotonin Neuron Depletion on Arterial Blood Pressure Regulation in Young Rats

Circulation ◽

10.1161/circ.130.suppl_2.15839 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Jennifer Magnusson ◽

Kevin Cummings

Keyword(s):

Blood Pressure ◽

Arterial Blood Pressure ◽

Recovery Period ◽

Sudden Infant Death ◽

Sudden Infant ◽

Sprague Dawley ◽

Baroreflex Control ◽

Hypoxic Conditions ◽

Arterial Blood

Infants dying of Sudden Infant Death Syndrome (SIDS) have reduced brainstem serotonin (5-hydroxytryptamine, 5-HT) where some cases die following episodes of severe bradycardia and hypoxemia. The specific role of central 5-HT in resting arterial blood pressure (BP) and on baroreflex sensitivity during neonatal life has not been studied. In adult animals, systemic depletion of 5-HT increases BP with no effect on heart rate (HR) and reduces the sensitivity of the baroreflex. Other studies have also shown that a loss of central 5-HT beginning in embryogenesis reduces resting BP and HR in adulthood. Based on these reports, we hypothesized that loss of brainstem 5-HT neurons in the neonatal period would reduce baseline BP and HR as well as reduce baroreflex gain. To test this, we utilized 3-week old Sprague Dawley rats treated centrally with 5,7-dihydroxytryptamine (5,7-DHT, n=4; ~120 ug in saline, i.c.v.), a chemical that is toxic to serotonergic neurons. Littermate controls were injected with saline (CTRL, n=5, ~3ul, i.c.v.). We measured BP with a femoral artery catheter. HR was derived from BP. Following a recovery period, we measured resting variables for 15 minutes and then injected phenylephrine (PE; 3mg/kg s.c.) followed by sodium nitroprusside (SNP; 2.5mg/kg s.c.), separated by 15 minutes, to induce pressor or depressor responses, respectively. For both responses, baroreflex gain was calculated as the [[Unable to Display Character: ∆]]HR at the maximum [[Unable to Display Character: ∆]]BP following drug injection. We found that a loss of 5-HT neurons did not alter baseline BP (p>0.05) but did reduce baseline HR when compared to control littermates (p<0.02). 5-HT neuron deficiency tended to reduce baroreflex gain in response to PE (CTRL: -2.756 ± 0.483 beats/mmHg; 5,7-DHT: -1.499 ± 0.348 beats/mmHg; p=0.058), but not SNP (CTRL: -2.408 ± 0.351 beats/mmHg; 5,7-DHT: -3.316 ± 1.214 beats/mmHg; p>0.05). Our data indicate that brainstem 5-HT maintains resting HR, and is involved in baroreflex control of HR in response to hypertensive stimuli. Reduced brainstem 5-HT may predispose an infant to SIDS via altered autonomic control of BP and HR. The role of 5-HT in BP regulation during hypoxic conditions remains to be elucidated.

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