Publications by authors named "Lisa A Palmer"

37 Publications

NADPH diaphorase detects S-nitrosylated proteins in aldehyde-treated biological tissues.

Sci Rep 2020 12 3;10(1):21088. Epub 2020 Dec 3.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH, 44106, USA.

NADPH diaphorase is used as a histochemical marker of nitric oxide synthase (NOS) in aldehyde-treated tissues. It is thought that the catalytic activity of NOS promotes NADPH-dependent reduction of nitro-blue tetrazolium (NBT) to diformazan. However, it has been argued that a proteinaceous factor other than NOS is responsible for producing diformazan in aldehyde-treated tissues. We propose this is a NO-containing factor such as an S-nitrosothiol and/or a dinitrosyl-iron (II) cysteine complex or nitrosated proteins including NOS. We now report that (1) S-nitrosothiols covalently modify both NBT and TNBT, but only change the reduction potential of NBT after modification, (2) addition of S-nitrosothiols or β- or α-NADPH to solutions of NBT did not elicit diformazan, (3) addition of S-nitrosothiols to solutions of NBT plus β- or α-NADPH elicited rapid formation of diformazan in the absence or presence of paraformaldehyde, (4) addition of S-nitrosothiols to solutions of NBT plus β- or α-NADP did not produce diformazan, (5) S-nitrosothiols did not promote NADPH-dependent reduction of tetra-nitro-blue tetrazolium (TNBT) in which all four phenolic rings are nitrated, (6) cytoplasmic vesicles in vascular endothelial cells known to stain for NADPH diaphorase were rich in S-nitrosothiols, and (7) procedures that accelerate decomposition of S-nitrosothiols, markedly reduced NADPH diaphorase staining in tissue sections subsequently subjected to paraformaldehyde fixation. Our results suggest that NADPH diaphorase in aldehyde-fixed tissues is not enzymatic but is due to the presence of NO-containing factors (free SNOs or nitrosated proteins such as NOS), which promote NADPH-dependent reduction of NBT to diformazan.
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http://dx.doi.org/10.1038/s41598-020-78107-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713249PMC
December 2020

The institutional repository landscape in medical schools and academic health centers: a 2018 snapshot view and analysis.

J Med Libr Assoc 2019 Oct 1;107(4):488-498. Epub 2019 Oct 1.

Collection Development/Special Projects Librarian, Galter Health Sciences Library & Learning Center, Northwestern University Feinberg School of Medicine, Chicago, IL,

Objective: This study uses survey research methods to gain a deeper understanding of the institutional repository (IR) landscape in medical schools and academic health centers.

Methods: Members of the Association of Academic Health Sciences Libraries (AAHSL) were surveyed about their IRs. The authors used a mixed-methods approach of a survey and qualitative content analysis to identify common themes.

Results: Survey results indicate that a large majority of responding medical schools and academic health centers have or are implementing an IR (35 out of 50, 70%). Of these, 60% (21 institutions) participate in an institution-wide IR rather than administer their own repositories. Much of the archived content is grey literature that has not already been published, but the percentage of original content varies greatly among institutions. The majority (57.1%) of respondent institutions are not considering an open access policy or mandate. Most institutions (71.4%) reported that repository staff are depositing materials on behalf of users. DSpace and bepress Digital Commons are the most popular repository platforms in this community. The planned enhancements that were most frequently reported were implementing a discovery layer and ORCID integration. The majority of respondents (54.3%) do not plan to migrate to a different platform in the foreseeable future. Analysis of respondent comments identified the following themes: integration, redundancy, and reporting; alternatives and exploration; uniqueness; participation; and funding and operations.

Conclusions: The study results capture a view of the IR landscape in medical schools and academic health centers and help readers understand what services their peers have in place as well as their plans for future developments.
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http://dx.doi.org/10.5195/jmla.2019.653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774547PMC
October 2019

S-nitrosylation of endothelial nitric oxide synthase impacts erectile function.

Int J Impot Res 2019 Jan 20;31(1):31-38. Epub 2018 Aug 20.

Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.

Neuronal and endothelial nitric oxide synthases (nNOS and eNOS respectively) play major roles in generating the nitric oxide bioactivity necessary for erectile function. S-nitrosylation has been shown to regulate NOS activity. The presence of S-nitrosylated NOS in the penis and the impact of NOS S-nitrosylation/denitrosylation on erectile function were examined. S-nitrosylated forms of NOS were identified by biotin-switch assay followed by western blot analysis. Erectile function in S-nitrosoglutathione reductase deficient (GSNO) and null (GSNO) mice were assessed by continuous cavernous nerve electrical stimulation (CCNES). Glutathione ethyl ester (GSHee) was used to manipulate S-nitrosylated NOS levels. Immunohistological and immunofluorescence analyses were used to identify the location of eNOS and GSNO-R in corporal tissue. eNOS and nNOS were S-nitrosylated in unstimulated penises of the mice. CCNES resulted in a time-dependent increase in eNOS S-nitrosylation with peak eNOS S-nitrosylation observed during detumescence. S-nitrosylated nNOS levels were unchanged. Intracorporal injection of GSHee reduced S-nitrosylated eNOS levels, enhancing time to maximum intracorporal pressure (ICP). eNOS and GSNO-R co-localize to the endothelium of the corpus cavernosum in the mouse and the human. ICP measurements obtained during CCNES demonstrate GSNO-R and GSNO-R animals cannot maintain an elevated ICP. Results suggest eNOS S-nitrosylation/denitrosylation is an important mechanism regulating eNOS activity during erectile function. GSNO-R is a key enzyme involved in the eNOS denitrosylation. The increase in eNOS S-nitrosylation (inactivation) observed with tumescence may begin a cycle leading to detumescence. Clinically this may indicate that alterations in the balance of S-nitrosylation/denitrosylation either directly or indirectly contribute to erectile dysfunction.
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http://dx.doi.org/10.1038/s41443-018-0056-0DOI Listing
January 2019

Mitochondrial protein S-nitrosation protects against ischemia reperfusion-induced denervation at neuromuscular junction in skeletal muscle.

Free Radic Biol Med 2018 03 9;117:180-190. Epub 2018 Feb 9.

Departments of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Departments of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Departments of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Electronic address:

Deterioration of neuromuscular junction (NMJ) integrity and function is causal to muscle atrophy and frailty, ultimately hindering quality of life and increasing the risk of death. In particular, NMJ is vulnerable to ischemia reperfusion (IR) injury when blood flow is restricted followed by restoration. However, little is known about the underlying mechanism(s) and hence the lack of effective interventions. New evidence suggests that mitochondrial oxidative stress plays a causal role in IR injury, which can be precluded by enhancing mitochondrial protein S-nitrosation (SNO). To elucidate the role of IR and mitochondrial protein SNO in skeletal muscle, we utilized a clinically relevant model and showed that IR resulted in significant muscle and motor nerve injuries with evidence of elevated muscle creatine kinase in the serum, denervation at NMJ, myofiber degeneration and regeneration, as well as muscle atrophy. Interestingly, we observed that neuromuscular transmission improved prior to muscle recovery, suggesting the importance of the motor nerve in muscle functional recovery. Injection of a mitochondria-targeted S-nitrosation enhancing agent, MitoSNO, into ischemic muscle prior to reperfusion reduced mitochondrial oxidative stress in the motor nerve and NMJ, attenuated denervation at NMJ, and resulted in accelerated functional recovery of the muscle. These findings demonstrate that enhancing mitochondrial protein SNO protects against IR-induced denervation at NMJ in skeletal muscle and accelerates functional regeneration. This could be an efficacious intervention for protecting neuromuscular injury under the condition of IR and other related pathological conditions.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896769PMC
March 2018

Research evaluation support services in biomedical libraries.

J Med Libr Assoc 2018 01 2;106(1):1-14. Epub 2018 Jan 2.

Objective: The paper provides a review of current practices related to evaluation support services reported by seven biomedical and research libraries.

Methods: A group of seven libraries from the United States and Canada described their experiences with establishing evaluation support services at their libraries. A questionnaire was distributed among the libraries to elicit information as to program development, service and staffing models, campus partnerships, training, products such as tools and reports, and resources used for evaluation support services. The libraries also reported interesting projects, lessons learned, and future plans.

Results: The seven libraries profiled in this paper report a variety of service models in providing evaluation support services to meet the needs of campus stakeholders. The service models range from research center cores, partnerships with research groups, and library programs with staff dedicated to evaluation support services. A variety of products and services were described such as an automated tool to develop rank-based metrics, consultation on appropriate metrics to use for evaluation, customized publication and citation reports, resource guides, classes and training, and others. Implementing these services has allowed the libraries to expand their roles on campus and to contribute more directly to the research missions of their institutions.

Conclusions: Libraries can leverage a variety of evaluation support services as an opportunity to successfully meet an array of challenges confronting the biomedical research community, including robust efforts to report and demonstrate tangible and meaningful outcomes of biomedical research and clinical care. These services represent a transformative direction that can be emulated by other biomedical and research libraries.
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http://dx.doi.org/10.5195/jmla.2018.205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764574PMC
January 2018

Phenotype of asthmatics with increased airway S-nitrosoglutathione reductase activity.

Eur Respir J 2015 Jan 30;45(1):87-97. Epub 2014 Oct 30.

Dept of Paediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH, USA

S-Nitrosoglutathione is an endogenous airway smooth muscle relaxant. Increased airway S-nitrosoglutathione breakdown occurs in some asthma patients. We asked whether patients with increased airway catabolism of this molecule had clinical features that distinguished them from other asthma patients. We measured S-nitrosoglutathione reductase expression and activity in bronchoscopy samples taken from 66 subjects in the Severe Asthma Research Program. We also analysed phenotype and genotype data taken from the program as a whole. Airway S-nitrosoglutathione reductase activity was increased in asthma patients (p=0.032). However, only a subpopulation was affected and this subpopulation was not defined by a "severe asthma" diagnosis. Subjects with increased activity were younger, had higher IgE and an earlier onset of symptoms. Consistent with a link between S-nitrosoglutathione biochemistry and atopy: 1) interleukin 13 increased S-nitrosoglutathione reductase expression and 2) subjects with an S-nitrosoglutathione reductase single nucleotide polymorphism previously associated with asthma had higher IgE than those without this single nucleotide polymorphism. Expression was higher in airway epithelium than in smooth muscle and was increased in regions of the asthmatic lung with decreased airflow. An early-onset, allergic phenotype characterises the asthma population with increased S-nitrosoglutathione reductase activity.
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http://dx.doi.org/10.1183/09031936.00042414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283933PMC
January 2015

Hemoglobin α/eNOS coupling at myoendothelial junctions is required for nitric oxide scavenging during vasoconstriction.

Arterioscler Thromb Vasc Biol 2014 Dec 2;34(12):2594-600. Epub 2014 Oct 2.

From the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.

Objective: Hemoglobin α (Hb α) and endothelial nitric oxide synthase (eNOS) form a macromolecular complex at myoendothelial junctions; the functional role of this interaction remains undefined. To test if coupling of eNOS and Hb α regulates nitric oxide signaling, vascular reactivity, and blood pressure using a mimetic peptide of Hb α to disrupt this interaction.

Approach And Results: In silico modeling of Hb α and eNOS identified a conserved sequence of interaction. By mutating portions of Hb α, we identified a specific sequence that binds eNOS. A mimetic peptide of the Hb α sequence (Hb α X) was generated to disrupt this complex. Using in vitro binding assays with purified Hb α and eNOS and ex vivo proximity ligation assays on resistance arteries, we have demonstrated that Hb α X significantly decreased interaction between eNOS and Hb α. Fluorescein isothiocyanate labeling of Hb α X revealed localization to holes in the internal elastic lamina (ie, myoendothelial junctions). To test the functional effects of Hb α X, we measured cyclic guanosine monophosphate and vascular reactivity. Our results reveal augmented cyclic guanosine monophosphate production and altered vasoconstriction with Hb α X. To test the in vivo effects of these peptides on blood pressure, normotensive and hypertensive mice were injected with Hb α X, which caused a significant decrease in blood pressure; injection of Hb α X into eNOS(-/-) mice had no effect.

Conclusions: These results identify a novel sequence on Hb α that is important for Hb α/eNOS complex formation and is critical for nitric oxide signaling at myoendothelial junctions.
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http://dx.doi.org/10.1161/ATVBAHA.114.303974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239174PMC
December 2014

Enhanced non-eupneic breathing following hypoxic, hypercapnic or hypoxic-hypercapnic gas challenges in conscious mice.

Respir Physiol Neurobiol 2014 Dec 19;204:147-59. Epub 2014 Sep 19.

Department of Pediatrics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4984, USA. Electronic address:

C57BL6 mice display non-eupneic breathing and spontaneous apneas during wakefulness and sleep as well as markedly disordered breathing following cessation of a hypoxic challenge. We examined whether (1) C57BL6 mice display marked non-eupneic breathing following hypercapnic or hypoxic-hypercapnic challenges, and (2) compared the post-hypoxia changes in non-eupneic breathing of C57BL6 mice to those of B6AF1 (57BL6 dam × A/J sire) and Swiss-Webster mice, which display different ventilatory responses than C57BL6 mice. C57BL6 mice displayed marked increases in respiratory frequency and non-eupneic breathing upon return to room-air after hypoxic (10% O2, 90% N2), hypercapnic (5% CO2, 21% O2 and 74% N2) and hypoxic-hypercapnic (10% O2, 5% CO2 and 85% N2) challenges. B6AF1 mice displayed less tachypnea and reduced non-eupneic breathing post-hypoxia, whereas Swiss-Webster mice displayed robust tachypnea with minimal increases in non-eupneic breathing post-hypoxia. These studies demonstrate that non-eupneic breathing increases after physiologically-relevant hypoxic-hypercapnic challenge in C57BL6 mice and suggest that further studies with these and B6AF1 and Swiss-Webster mice will help define the genetics of non-eupneic breathing.
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http://dx.doi.org/10.1016/j.resp.2014.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252883PMC
December 2014

Morphine has latent deleterious effects on the ventilatory responses to a hypoxic challenge.

Open J Mol Integr Physiol 2013 Nov;3(4):166-180

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

The aim of this study was to determine whether morphine depresses the ventilatory responses elicited by a hypoxic challenge (10% O, 90% N) in conscious rats at a time when the effects of morphine on arterial blood gas (ABG) chemistry, Alveolar-arterial (A-a) gradient and minute ventilation (V) had completely subsided. In vehicle-treated rats, each episode of hypoxia stimulated ventilatory function and the responses generally subsided during each normoxic period. Morphine (5 mg/kg, i.v.) induced an array of depressant effects on ABG chemistry, A-a gradient and V (via decreases in tidal volume). Despite resolution of these morphine-induced effects, the first episode of hypoxia elicited substantially smaller increases in V than in vehicle-treated rats, due mainly to smaller increases in frequency of breathing. The pattern of ventilatory responses during subsequent episodes of hypoxia and normoxia changed substantially in morphine-treated rats. It is evident that morphine has latent deleterious effects on ventilatory responses elicited by hypoxic challenge.
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http://dx.doi.org/10.4236/ojmip.2013.34022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103751PMC
November 2013

Morphine has latent deleterious effects on the ventilatory responses to a hypoxic-hypercapnic challenge.

Open J Mol Integr Physiol 2013 Aug;3(3):134-145

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

This study explored the concept that morphine has latent deleterious actions on the ventilatory control systems that respond to a hypoxic-hypercapnic challenge. In this study, we examined the ventilatory responses elicited by hypoxic-hypercapnic challenge in conscious rats at a time when the effects of morphine (10 mg/kg) on arterial blood-gas chemistry and minute ventilation had subsided. Morphine induced pronounced changes in arterial blood-gas chemistry (e.g., an increase in pCO, decreases in pO and sO) and decreases in minute ventilation. Despite the complete resolution of the morphine-induced changes in arterial blood-gas chemistry and minute ventilation and almost complete resolution of the effects on peak inspiratory flow and peak expiratory flow, subsequent exposure to hypoxic-hypercapnic challenge elicited markedly blunted increases in minute ventilation and in peak inspiratory and expiratory flows. These findings demonstrate that (1) the changes in arterial blood-gas chemistry elicited by morphine parallel changes in minute ventilation rather than PIF and PEF, and (2) morphine has latent untoward effects on the ventilatory responses to hypoxic-hypercapnic challenge. These novel findings raise the possibility that patients deemed to have recovered from the acute ventilatory depressant effects of morphine may still be susceptible to the latent effects of this opioid analgesic. The mechanisms underlying these latent effects remain to be elucidated.
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http://dx.doi.org/10.4236/ojmip.2013.33019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103749PMC
August 2013

Hypoxia-induced changes in protein s-nitrosylation in female mouse brainstem.

Am J Respir Cell Mol Biol 2015 Jan;52(1):37-45

1 Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia.

Exposure to hypoxia elicits an increase in minute ventilation that diminishes during continued exposure (roll-off). Brainstem N-methyl-D-aspartate receptors (NMDARs) and neuronal nitric oxide synthase (nNOS) contribute to the initial hypoxia-induced increases in minute ventilation. Roll-off is regulated by platelet-derived growth factor receptor-β (PDGFR-β) and S-nitrosoglutathione (GSNO) reductase (GSNOR). S-nitrosylation inhibits activities of NMDAR and nNOS, but enhances GSNOR activity. The importance of S-nitrosylation in the hypoxic ventilatory response is unknown. This study confirms that ventilatory roll-off is virtually absent in female GSNOR(+/-) and GSNO(-/-) mice, and evaluated the location of GSNOR in female mouse brainstem, and temporal changes in GSNOR activity, protein expression, and S-nitrosylation status of GSNOR, NMDAR (1, 2A, 2B), nNOS, and PDGFR-β during hypoxic challenge. GSNOR-positive neurons were present throughout the brainstem, including the nucleus tractus solitarius. Protein abundances for GSNOR, nNOS, all NMDAR subunits and PDGFR-β were not altered by hypoxia. GSNOR activity and S-nitrosylation status temporally increased with hypoxia. In addition, nNOS S-nitrosylation increased with 3 and 15 minutes of hypoxia. Changes in NMDAR S-nitrosylation were detected in NMDAR 2B at 15 minutes of hypoxia. No hypoxia-induced changes in PDGFR-β S-nitrosylation were detected. However, PDGFR-β phosphorylation increased in the brainstems of wild-type mice during hypoxic exposure (consistent with roll-off), whereas it did not rise in GSNOR(+/-) mice (consistent with lack of roll-off). These data suggest that: (1) S-nitrosylation events regulate hypoxic ventilatory response; (2) increases in S-nitrosylation of NMDAR 2B, nNOS, and GSNOR may contribute to ventilatory roll-off; and (3) GSNOR regulates PDGFR-β phosphorylation.
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http://dx.doi.org/10.1165/rcmb.2013-0359OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370248PMC
January 2015

Low-dose morphine elicits ventilatory excitant and depressant responses in conscious rats: Role of peripheral μ-opioid receptors.

Open J Mol Integr Physiol 2013 Aug;3(3):111-124

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

The systemic administration of morphine affects ventilation via a mixture of central and peripheral actions. The aims of this study were to characterize the ventilatory responses elicited by a low dose of morphine in conscious rats; to determine whether tolerance develops to these responses; and to determine the potential roles of peripheral μ-opioid receptors (μ-ORs) in these responses. Ventilatory parameters were monitored via unrestrained whole-body plethysmography. Conscious male Sprague-Dawley rats received an intravenous injection of vehicle or the peripherally-restricted μ-OR antagonist, naloxone methiodide (NLXmi), and then three successive injections of morphine (1 mg/kg) given 30 min apart. The first injection of morphine in vehicle-treated rats elicited an array of ventilatory excitant (i.e., increases in frequency of breathing, minute volume, respiratory drive, peak inspiratory and expiratory flows, accompanied by decreases in inspiratory time and end inspiratory pause) and inhibitory (i.e., a decrease in tidal volume and an increase in expiratory time) responses. Subsequent injections of morphine elicited progressively and substantially smaller responses. The pattern of ventilatory responses elicited by the first injection of morphine was substantially affected by pretreatment with NLXmi whereas NLXmi minimally affected the development of tolerance to these responses. Low-dose morphine elicits an array of ventilatory excitant and depressant effects in conscious rats that are subject to the development of tolerance. Many of these initial actions of morphine appear to involve activation of peripheral μ-ORs whereas the development of tolerance to these responses does not.
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http://dx.doi.org/10.4236/ojmip.2013.33017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041292PMC
August 2013

The role of regulatory proteins and S-nitrosylation of endothelial nitric oxide synthase in the human clitoris: implications for female sexual function.

J Sex Med 2014 Aug 16;11(8):1927-35. Epub 2014 May 16.

Department of Urology, University of Virginia, Charlottesville, VA, USA.

Introduction: During female sexual arousal, clitoral blood flow is controlled by endothelial nitric oxide synthase (eNOS) and its product, nitric oxide (NO). The mechanisms regulating eNOS activity and NO bioavailability in the clitoris are largely unknown.

Aim: To identify proteins involved in regulation of eNOS activity within the clitoris and to evaluate the effects of S-nitrosoglutathione reductase (GSNO-R) and eNOS nitrosylation/denitrosylation on clitoral blood flow.

Methods: Immunohistochemistry for eNOS, caveolin-1 (Cav1), heat shock protein-90 (Hsp90), phosphodiesterase type 5 (PDE5), GSNO-R, and soluble guanylate cyclase (sGC) was performed on human and murine clitoral tissue. Western blot analysis was performed for eNOS, phosphorylated eNOS (phospho-eNOS, Ser1177), Cav1, Hsp90, sGC, PDE5, phosphoinositide 3-kinase (PI3K), Akt (protein kinase B), and GSNO-R on protein from human clitoral tissue. A biotin switch assay was used to analyze the S-nitrosylation of eNOS, nNOS, and GSNO-R. Clitoral blood flow was measured in wild-type and GSNO-R(-/-) mice at baseline and during cavernous nerve electrical stimulation (CNES).

Main Outcome Measures: Localization of eNOS regulatory proteins and clitoral blood flow.

Results: eNOS and GSNO-R co-localized to the vascular endothelium and sinusoids of human clitoral tissue. Immunohistochemistry also localized Cav1 and Hsp90 to the endothelium and PDE5 and sGC to the trabecular smooth muscle. Expression of S-nitrosylated (SNO)-eNOS and SNO-GSNO-R was detected by biotin switch assays. Wild-type control mice exhibited increased clitoral blood flow with CNES whereas GSNO-R(-/-) animals failed to show an increase in blood flow.

Conclusions: Several key eNOS regulatory proteins are present in the clitoral tissue in a cellular specific pattern. S-nitrosylation of eNOS may also represent a key regulatory mechanism governing eNOS activation/deactivation since mice deficient in GSNO-R failed to increase clitoral blood flow. Additional studies are necessary to define the role of S-nitrosylation in the genital vascular response and its subsequent impact on female sexual function.
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http://dx.doi.org/10.1111/jsm.12576DOI Listing
August 2014

Essential role of hemoglobin beta-93-cysteine in posthypoxia facilitation of breathing in conscious mice.

J Appl Physiol (1985) 2014 May 7;116(10):1290-9. Epub 2014 Mar 7.

Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, Ohio.

When erythrocyte hemoglobin (Hb) is fully saturated with O2, nitric oxide (NO) covalently binds to the cysteine 93 residue of the Hb β-chain (B93-CYS), forming S-nitrosohemoglobin. Binding of NO is allosterically coupled to the O2 saturation of Hb. As saturation falls, the NO group on B93-CYS is transferred to thiols in the erythrocyte, and in the plasma, forming circulating S-nitrosothiols. Here, we studied whether the changes in ventilation during and following exposure to a hypoxic challenge were dependent on erythrocytic B93-CYS. Studies were performed in conscious mice in which native murine Hb was replaced with human Hb (hB93-CYS mice) and in mice in which murine Hb was replaced with human Hb containing an alanine rather than cysteine at position 93 on the Bchain (hB93-ALA). Both strains expressed human γ-chain Hb, likely allowing a residual element of S-nitrosothiol-dependent signaling. While resting parameters and initial hypoxic (10% O2, 90% N2) ventilatory responses were similar in hB93-CYS mice and hB93-ALA mice, the excitatory ventilatory responses (short-term potentiation) that occurred once the mice were returned to room air were markedly diminished in hB93-ALA mice. Further, short-term potentiation responses were virtually absent in mice with bilateral transection of the carotid sinus nerves. These data demonstrate that hB93-CYS plays an essential role in mediating carotid sinus nerve-dependent short-term potentiation, an important mechanism for recovery from acute hypoxia.
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http://dx.doi.org/10.1152/japplphysiol.01050.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4044395PMC
May 2014

Loss of collectrin, an angiotensin-converting enzyme 2 homolog, uncouples endothelial nitric oxide synthase and causes hypertension and vascular dysfunction.

Circulation 2013 Oct 18;128(16):1770-80. Epub 2013 Sep 18.

Departments of Medicine (S.C., Q.Z., C.K.R., F.R.C., N.L.H., R.M.C., S.-S.J.S., T.H.L.), Molecular Physiology and Biophysics (M.B., S.M., A.C.S., B.E.I.), and Pediatrics (L.A.P.), University of Virginia, Charlottesville; Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC (L.C., R.G.); Department of Cardiovascular and Renal Research Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark (J.H., K.M., B.L.J.); and Department of Medicine, Salem Veterans Administration, Salem, VA (S.M.M.).

Background: Collectrin is an orphan member of the renin-angiotensin system and is a homolog of angiotensin-converting enzyme 2, sharing ≈50% sequence identity. Unlike angiotensin-converting enzyme 2, collectrin lacks any catalytic domain. Collectrin has been shown to function as a chaperone of amino acid transporters. In rodents, the renal expression of collectrin is increased after subtotal nephrectomy and during high-salt feeding, raising the question of whether collectrin has any direct role in blood pressure regulation.

Methods And Results: Using a susceptible genetic background, we demonstrate that deletion of collectrin results in hypertension, exaggerated salt sensitivity, and impaired pressure natriuresis. Collectrin knockout mice display impaired endothelium-dependent vasorelaxation that is associated with vascular remodeling, endothelial nitric oxide synthase uncoupling, decreased nitric oxide production, and increased superoxide generation. Treatment with Tempol, a superoxide scavenger, attenuates the augmented sodium sensitivity in collectrin knockout mice. We report for the first time that collectrin is expressed in endothelial cells. Furthermore, collectrin directly regulates l-arginine uptake and plasma membrane levels of CAT1 and y(+)LAT1 amino acid transporters in endothelial cells. Treatment with l-arginine modestly lowers blood pressure of collectrin knockout mice.

Conclusions: Collectrin is a consequential link between the transport of l-arginine and endothelial nitric oxide synthase uncoupling in hypertension.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.113.003301DOI Listing
October 2013

Co-activation of μ- and δ-opioid receptors elicits tolerance to morphine-induced ventilatory depression via generation of peroxynitrite.

Respir Physiol Neurobiol 2013 May 5;186(3):255-64. Epub 2013 Mar 5.

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

We determined whether pretreatment with (1) the μ-/δ-opioid receptor (μ-/δ-OR) antagonist, naloxone, (2) the δ1,2-OR antagonist, naltrindole, or (3) the peroxynitrite scavenger, d-penicillamine, affects the development of tolerance to the ventilatory depressant effects of morphine in rats. The injection of morphine in vehicle-pretreated rats decreased minute ventilation predominantly via decreases in tidal volume. Pretreatment with naloxone blunted the responses to morphine whereas pretreatment with naltrindole or d-penicillamine did not. A second injection of morphine, given one day later, elicited markedly smaller responses in vehicle rats whereas it elicited pronounced ventilatory depression in rats that were pretreated with naloxone, naltrindole or d-penicillamine (prior to morphine) the day before. Moreover, the ventilatory responses elicited by subsequent exposure to a hypoxic-hypercapnic challenge were markedly depressed in naloxone- or d-penicillamine-pretreated rats compared to vehicle-pretreated rats. These findings suggest that activation of μ- and δ-ORs causes tolerance to the ventilatory depressant effects of morphine at least partly via the generation of peroxynitrite.
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http://dx.doi.org/10.1016/j.resp.2013.02.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451624PMC
May 2013

Hypoxia-induced ventilatory responses in conscious mice: gender differences in ventilatory roll-off and facilitation.

Respir Physiol Neurobiol 2013 Feb 24;185(3):497-505. Epub 2012 Nov 24.

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

The aim of this study was to compare the ventilatory responses of C57BL6 female and male mice during a 15 min exposure to a hypoxic-hypercapnic (H-H) or a hypoxic (10% O(2), 90% N(2)) challenge and subsequent return to room air. The ventilatory responses to H-H were similar in males and females whereas there were pronounced gender differences in the ventilatory responses during and following hypoxic challenge. In males, the hypoxic response included initial increases in minute volume via increases in tidal volume and frequency of breathing. These responses declined substantially (roll-off) during hypoxic exposure. Upon return to room-air, relatively sustained increases in these ventilatory parameters (short-term potentiation) were observed. In females, the initial responses to hypoxia were similar to those in males whereas roll-off was greater and post-hypoxia facilitation was smaller than in males. The marked differences in ventilatory roll-off and post-hypoxia facilitation between female and male C57BL6 mice provide evidence that gender is of vital importance to ventilatory control.
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http://dx.doi.org/10.1016/j.resp.2012.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593587PMC
February 2013

Ventilatory responses during and following exposure to a hypoxic challenge in conscious mice deficient or null in S-nitrosoglutathione reductase.

Respir Physiol Neurobiol 2013 Feb 24;185(3):571-81. Epub 2012 Nov 24.

Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

Exposure to a hypoxic challenge increases ventilation in wild-type (WT) mice that diminish during the challenge (roll-off) whereas return to room air causes an increase in ventilation (short-term facilitation, STF). Since plasma and tissue levels of ventilatory excitant S-nitrosothiols such as S-nitrosoglutathione (GSNO) increase during hypoxia, this study examined whether (1) the initial increase in ventilation is due to generation of GSNO, (2) roll-off is due to increased activity of the GSNO degrading enzyme, GSNO reductase (GSNOR), and (3) STF is limited by GSNOR activity. Initial ventilatory responses to hypoxic challenge (10% O(2), 90% N(2)) were similar in WT, GSNO+/- and GSNO-/- mice. These responses diminished markedly during hypoxic challenge in WT mice whereas there was minimal roll-off in GSNOR+/- and GSNOR-/- mice. Finally, STF was greater in GSNOR+/- and GSNOR-/- mice than in WT mice (especially females). This study suggests that GSNOR degradation of GSNO is a vital step in the expression of ventilatory roll-off and that GSNOR suppresses STF.
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http://dx.doi.org/10.1016/j.resp.2012.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593598PMC
February 2013

Gender differences in S-nitrosoglutathione reductase activity in the lung.

PLoS One 2010 Nov 16;5(11):e14007. Epub 2010 Nov 16.

Department of Pediatrics, University of Virginia Health System, Charlottesville, Virginia, United States of America.

S-nitrosothiols have been implicated in the etiology of various pulmonary diseases. Many of these diseases display gender preferences in presentation or altered severity that occurs with puberty, the mechanism by which is unknown. Estrogen has been shown to influence the expression and activity of endothelial nitric oxide synthase (eNOS) which is associated with increased S-nitrosothiol production. The effects of gender hormones on the expression and activity of the de-nitrosylating enzyme S-nitrosoglutathione reductase (GSNO-R) are undefined. This report evaluates the effects of gender hormones on the activity and expression of GSNO-R and its relationship to N-acetyl cysteine (NAC)-induced pulmonary hypertension (PH). GSNO-R activity was elevated in lung homogenates from female compared to male mice. Increased activity was not due to changes in GSNO-R expression, but correlated with GSNO-R S-nitrosylation: females were greater than males. The ability of GSNO-R to be activated by S-nitrosylation was confirmed by: 1) the ability of S-nitrosoglutathione (GSNO) to increase the activity of GSNO-R in murine pulmonary endothelial cells and 2) reduced activity of GSNO-R in lung homogenates from eNOS(-/-) mice. Gender differences in GSNO-R activity appear to explain the difference in the ability of NAC to induce PH: female and castrated male animals are protected from NAC-induced PH. Castration results in elevated GSNO-R activity that is similar to that seen in female animals. The data suggest that GSNO-R activity is modulated by both estrogens and androgens in conjunction with hormonal regulation of eNOS to maintain S-nitrosothiol homeostasis. Moreover, disruption of this eNOS-GSNO-R axis contributes to the development of PH.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0014007PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2982841PMC
November 2010

Chemokine receptor CCR5 mediates alloimmune responses in graft-versus-host disease.

Biol Blood Marrow Transplant 2010 Mar 16;16(3):311-9. Epub 2009 Dec 16.

Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Allogeneic bone marrow transplantation (BMT) is an effective therapy for hematologic malignancies. However graft-versus-host disease (GVHD) is a major limiting factor for a successful patient outcome. GVHD is a result of alloimmune responses of donor T lymphocytes attacking the recipient's cells and tissues. Chemokine receptor CCR5 plays a role in solid organ allograft rejection and mediates murine GVHD pathogenesis. Herein, we report that infiltrating lymphocytes in the skin of human acute GVHD (aGVHD) samples are predominantly CCR5(+) T cells. In addition, we characterized the features of the CCR5 expression on alloreactive T lymphocytes. We found that the CCR5(+) population exhibits the characteristics of the activated effector T cell phenotype. CCR5 expression is upregulated upon allogenic stimulation, and CCR5(+) cells are proliferating with coexpression of T cell activation markers. Furthermore, the activated T cells producing inflammatory cytokine tumor necrosis factor (TNF)alpha, interleukin (IL)-2, or interferon (IFN)-gamma, are positive for CCR5. Thus, CCR5 is a marker for GVHD effector cells and CCR5(+) T cells are active participants in the pathogenesis of human aGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2009.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182111PMC
March 2010

Trends in health sciences library and information science research: an analysis of research publications in the Bulletin of the Medical Library Association and Journal of the Medical Library Association from 1991 to 2007.

J Med Libr Assoc 2009 07;97(3):203-11

Education and Research Services, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.

Objective: This study analyzed trends in research activity as represented in the published research in the leading peer-reviewed professional journal for health sciences librarianship.

Methodology: Research articles were identified from the Bulletin of the Medical Library Association and Journal of the Medical Library Association (1991-2007). Using content analysis and bibliometric techniques, data were collected for each article on the (1) subject, (2) research method, (3) analytical technique used, (4) number of authors, (5) number of citations, (6) first author affiliation, and (7) funding source. The results were compared to a previous study, covering the period 1966 to 1990, to identify changes over time.

Results: Of the 930 articles examined, 474 (51%) were identified as research articles. Survey (n = 174, 37.1%) was the most common methodology employed, quantitative descriptive statistics (n = 298, 63.5%) the most used analytical technique, and applied topics (n = 332, 70%) the most common type of subject studied. The majority of first authors were associated with an academic health sciences library (n = 264, 55.7%). Only 27.4% (n = 130) of studies identified a funding source.

Conclusion: This study's findings demonstrate that progress is being made in health sciences librarianship research. There is, however, room for improvement in terms of research methodologies used, proportion of applied versus theoretical research, and elimination of barriers to conducting research for practicing librarians.
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http://dx.doi.org/10.3163/1536-5050.97.3.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706445PMC
July 2009

Hypoxia-inducible factor-1alpha is constitutively expressed in murine Leydig cells and regulates 3beta-hydroxysteroid dehydrogenase type 1 promoter activity.

J Androl 2009 Mar-Apr;30(2):146-56. Epub 2008 Oct 16.

Department of Urology, University of Virginia, Charlottesville, VA 22908, USA.

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that plays an essential role in oxygen homeostasis. HIF-1alpha is constitutively made in cells; however, it is ubiquitinated and degraded under normoxic conditions. Hypoxia prevents the ubiquitination of HIF-1alpha, resulting in stabilization of the protein and activation of target genes. Because of its vascular arrangement and the high metabolic demand of spermatogenesis, the testis has been described previously as functioning on the brink of hypoxia; thus, we have hypothesized that HIF-1alpha is constitutively expressed and stabilized in the testis, where it could play a role in testicular homeostasis. Western blot analysis using nuclear proteins from liver, kidney, and testis revealed the presence of HIF-1alpha only in the testis. Immunohistochemistry confirmed this result and revealed that HIF-1alpha was specifically located in interstitial Leydig cells. Electromobility shift assays employing nuclear extracts from the TM3 Leydig cell line revealed that these cells express HIF-1alpha that is capable of binding DNA under normoxic conditions. Furthermore, we found that protein levels can be increased further when the TM3 cells are cultured under hypoxic conditions. Finally, transient transfections of TM3 Leydig cells revealed that the promoter of the mouse 3beta-hydroxysteroid dehydrogenase type 1 (Hsd3b1) gene, which encodes a key enzyme in testosterone production, is a potential target of HIF-1alpha. In conclusion, HIF-1alpha is constitutively present in the Leydig cells of the murine testis, where it potentially regulates Hsd3b1 transcription, and thus male reproductive function.
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http://dx.doi.org/10.2164/jandrol.108.006155DOI Listing
April 2009

SNO-hemoglobin and hypoxic vasodilation.

Nat Med 2008 Oct;14(10):1009; author reply 1009-10

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http://dx.doi.org/10.1038/nm1008-1009aDOI Listing
October 2008

Digitizing dissertations for an institutional repository: a process and cost analysis.

J Med Libr Assoc 2008 07;96(3):223-9

Technology Initiatives and Resource Management, Lamar Soutter Library, University of Massachusetts, Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.

Objective: This paper describes the Lamar Soutter Library's process and costs associated with digitizing 300 doctoral dissertations for a newly implemented institutional repository at the University of Massachusetts Medical School.

Methodology: Project tasks included identifying metadata elements, obtaining and tracking permissions, converting the dissertations to an electronic format, and coordinating workflow between library departments. Each dissertation was scanned, reviewed for quality control, enhanced with a table of contents, processed through an optical character recognition function, and added to the institutional repository.

Results: Three hundred and twenty dissertations were digitized and added to the repository for a cost of $23,562, or $0.28 per page. Seventy-four percent of the authors who were contacted (n = 282) granted permission to digitize their dissertations. Processing time per title was 170 minutes, for a total processing time of 906 hours. In the first 17 months, full-text dissertations in the collection were downloaded 17,555 times.

Conclusion: Locally digitizing dissertations or other scholarly works for inclusion in institutional repositories can be cost effective, especially if small, defined projects are chosen. A successful project serves as an excellent recruitment strategy for the institutional repository and helps libraries build new relationships. Challenges include workflow, cost, policy development, and copyright permissions.
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http://dx.doi.org/10.3163/1536-5050.96.3.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2479051PMC
July 2008

S-nitrosothiol assays that avoid the use of iodine.

Methods Enzymol 2008 ;440:157-76

Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

S-Nitrosylation is a ubiquitous signaling process in biological systems. Research regarding this signaling has been hampered, however, by assays that lack sensitivity and specificity. In particular, iodine-based assays for S-nitrosothiols (1) produce nitrosyliodide, a potent nitrosating agent that can be lost to reactions in the biological sample being studied; (2) require pretreatment of biological samples with several reagents that react with proteins, artifactually forming or breaking S-NO bonds before the assay; and (3) are not sensitive or specific for nitrogen oxides in biological samples, reporting a wide range of different concentrations and falsely reporting NO-modified proteins, to be nitrite. These data, therefore, suggest that iodine-based assays should never be used for biological S-nitrosothiols. There are other assays that provide reasonably sensitive and accurate data regarding biological S-nitrosothiols, including assays based on mass spectrometry, spectrophotometry, chemiluminescence, fluorescence, and immunostaining. Each assay, however, has limitations and should be quantitatively complemented by separate assays. Continued improvement in assays will facilitate improved understanding of S-nitrosylation signaling.
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http://dx.doi.org/10.1016/S0076-6879(07)00809-9DOI Listing
June 2008

S-nitrosothiols signal hypoxia-mimetic vascular pathology.

J Clin Invest 2007 Sep;117(9):2592-601

Department of Pediatrics, University of Virginia School of Medicine, Virginia 22908, USA.

NO transfer reactions between protein and peptide cysteines have been proposed to represent regulated signaling processes. We used the pharmaceutical antioxidant N-acetylcysteine (NAC) as a bait reactant to measure NO transfer reactions in blood and to study the vascular effects of these reactions in vivo. NAC was converted to S-nitroso-N-acetylcysteine (SNOAC), decreasing erythrocytic S-nitrosothiol content, both during whole-blood deoxygenation ex vivo and during a 3-week protocol in which mice received high-dose NAC in vivo. Strikingly, the NAC-treated mice developed pulmonary arterial hypertension (PAH) that mimicked the effects of chronic hypoxia. Moreover, systemic SNOAC administration recapitulated effects of both NAC and hypoxia. eNOS-deficient mice were protected from the effects of NAC but not SNOAC, suggesting that conversion of NAC to SNOAC was necessary for the development of PAH. These data reveal an unanticipated adverse effect of chronic NAC administration and introduce a new animal model of PAH. Moreover, evidence that conversion of NAC to SNOAC during blood deoxygenation is necessary for the development of PAH in this model challenges conventional views of oxygen sensing and of NO signaling.
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http://dx.doi.org/10.1172/JCI29444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1952618PMC
September 2007

Akt-mediated activation of HIF-1 in pulmonary vascular endothelial cells by S-nitrosoglutathione.

Am J Respir Cell Mol Biol 2007 Sep 31;37(3):255-63. Epub 2007 May 31.

Department of Pediatrics, Divisions of Critical Care and Respiratory Medicine, University of Virginia School of Medicine, P.O. Box 801366, Charlottesville, VA 22908, USA.

S-nitrosoglutathione (GSNO) stabilizes the alpha-subunit of hypoxia inducible factor-1 (HIF-1) in normoxic cells, but not in the presence of PI3K inhibitors. In this report, the biochemical pathway by which GSNO alters PI3K/Akt activity to modify HIF-1 expression was characterized in Cos cells and primary pulmonary vascular endothelial cells. GSNO increased Akt kinase activity--and downstream HIF-1alpha protein accumulation and DNA-binding activity--in a dose- and time-dependent manner. The PI3K inhibitors, wortmannin and LY294002, blocked these responses. Neither glutathione nor 8-bromo-cyclic GMP mimicked the GSNO-induced increases in Akt kinase activity. GSNO-induced Akt kinase activity and downstream HIF-1alpha stabilization were blocked by acivicin, an inhibitor of gamma-glutamyl transpeptidase (gammaGT), a transmembrane protein that can translate extracellular GSNO to intracellular S-nitrosocysteinylglycine. Dithiothreitol blocked GSNO-induced Akt kinase activity and HIF-1alpha stabilization. Moreover, the 3'-phosphatase of phosphoinositides, PTEN (phosphatase and tensin homolog deleted on chromosome ten) was S-nitrosylated by GSNO in pulmonary arterial endothelial cells, which was reversed by dithiothreitol and ultraviolet light. Interestingly, the abundance of S-nitrosylated PTEN also correlated inversely with PTEN activity. Taken together, these results suggest that GSNO induction of Akt appears to be mediated by S-nitrosylation chemistry rather than classic NO signaling through guanylate cyclase/cGMP. We speculate that gammaGT-dependent activation of Akt and subsequent activation of HIF-1 in vascular beds may be relevant to the regulation of HIF-1-dependent gene expression in conditions associated with oxyhemoglobin deoxygenation, as opposed to profoundly low Po(2), in the pulmonary vasculature.
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http://dx.doi.org/10.1165/rcmb.2006-0289SMDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994227PMC
September 2007