scholarly journals Superoxide dismutase restores eNOS expression and function in resistance pulmonary arteries from neonatal lambs with persistent pulmonary hypertension

2008 ◽  
Vol 295 (6) ◽  
pp. L979-L987 ◽  
Author(s):  
Kathryn N. Farrow ◽  
Satyan Lakshminrusimha ◽  
William J. Reda ◽  
Stephen Wedgwood ◽  
Lyubov Czech ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Newborn Infants ◽  
Persistent Pulmonary Hypertension ◽  
Ros Production ◽  
Enos Expression ◽  
Neonatal Lambs ◽  
And Function ◽  
Endothelial Nitric Oxide ◽  
The Impact

Endothelial nitric oxide (NO) synthase (eNOS) expression and activity are decreased in fetal lambs with persistent pulmonary hypertension (PPHN). We sought to determine the impact of mechanical ventilation with O2 with or without inhaled NO (iNO) or recombinant human SOD (rhSOD) on eNOS in the ductal ligation model of PPHN. PPHN lambs and age-matched controls were ventilated with 100% O2 for 24 h alone or combined with 20 ppm iNO continuously or a single dose of rhSOD (5 mg/kg) given intratracheally at delivery. In 1-day spontaneously breathing lambs, eNOS expression in resistance pulmonary arteries increased relative to fetal levels. eNOS expression increased in control lambs ventilated with 100% O2, but not in PPHN lambs. Addition of iNO or rhSOD increased eNOS expression and decreased generation of reactive oxygen species (ROS) in PPHN lambs relative to those ventilated with 100% O2 alone. However, only rhSOD restored eNOS function, increased tetrahydrobiopterin (BH4), a critical cofactor for eNOS function, and restored GTP cyclohydrolase I expression in isolated vessels and lungs from PPHN lambs. These data suggest that ventilation of PPHN lambs with 100% O2 increases ROS production, blunts postnatal increases in eNOS expression, and decreases available BH4 in PPHN lambs. Although the addition of iNO or rhSOD diminished ROS production and increased eNOS expression, only rhSOD improved eNOS function and levels of available BH4. Thus therapies designed to decrease oxidative stress and restore eNOS coupling, such as rhSOD, may prove useful in the treatment of PPHN in newborn infants.

scholarly journals SOD and inhaled nitric oxide normalize phosphodiesterase 5 expression and activity in neonatal lambs with persistent pulmonary hypertension

2010 ◽  
Vol 299 (1) ◽  
pp. L109-L116 ◽  
Author(s):  
Kathryn N. Farrow ◽  
Satyan Lakshminrusimha ◽  
Lyubov Czech ◽  
Beezly S. Groh ◽  
Sylvia F. Gugino ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Newborn Infants ◽  
Inhaled Nitric Oxide ◽  
Persistent Pulmonary Hypertension ◽  
The Impact ◽  
Phosphodiesterase 5 ◽  
Expression And Activity

Phosphodiesterase 5 (PDE5) and soluble guanylate cyclase (sGC) are key regulators of cGMP and pulmonary vascular tone. We sought to determine the impact of mechanical ventilation with O2 with or without inhaled nitric oxide (iNO) or recombinant human Cu/Zn SOD (rhSOD) on sGC, PDE5, and cGMP in the ovine ductal ligation model of persistent pulmonary hypertension of the newborn (PPHN). PPHN lambs were ventilated with 100% O2 for 24 h alone or combined with either inhalation of 20 parts per million (ppm) iNO continuously or a single intratracheal dose of rhSOD (5 mg/kg). Ventilated PPHN lambs were compared with PPHN fetuses, control fetuses, and 1-day-old spontaneously breathing lambs (1DSB). In the small pulmonary arteries of 1DSB lambs, sGC expression increased, PDE5 expression decreased, and cGMP concentrations increased relative to fetal levels. In PPHN lambs ventilated with 100% O2, sGC activity increased to levels comparable with 1DSB levels. However, PDE5 expression and activity increased, and cGMP levels remained at fetal levels. Addition of either iNO or rhSOD decreased PDE5 expression and activity in PPHN lambs and increased cGMP levels to levels comparable with 1DSB lambs. These data suggest that ventilation of PPHN lambs with 100% O2 impairs cGMP-mediated vasodilation in part due to increased PDE5 expression and activity. The addition of either iNO or rhSOD normalized PDE5 and cGMP levels. Thus therapies designed to decrease PDE5 and increase cGMP, such as iNO and rhSOD, may prove useful in the treatment of PPHN in newborn infants.

scholarly journals Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn

2012 ◽  
Vol 302 (6) ◽  
pp. L616-L626 ◽  
Author(s):  
Stephen Wedgwood ◽  
Satyan Lakshminrusimha ◽  
Kathryn N. Farrow ◽  
Lyubov Czech ◽  
Sylvia F. Gugino ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Nadph Oxidase ◽  
Ductus Arteriosus ◽  
Pulmonary Arteries ◽  
Oxidase Inhibitor ◽  
No Synthase ◽  
Persistent Pulmonary Hypertension ◽  
No Donor ◽  
Oxidase Inhibition ◽  
Endothelial Nitric Oxide

NADPH oxidase is a major source of superoxide anions in the pulmonary arteries (PA). We previously reported that intratracheal SOD improves oxygenation and restores endothelial nitric oxide (NO) synthase (eNOS) function in lambs with persistent pulmonary hypertension of the newborn (PPHN). In this study, we determined the effects of the NADPH oxidase inhibitor apocynin on oxygenation, reactive oxygen species (ROS) levels, and NO signaling in PPHN lambs. PPHN was induced in lambs by antenatal ligation of the ductus arteriosus 9 days prior to delivery. Lambs were treated with vehicle or apocynin (3 mg/kg intratracheally) at birth and then ventilated with 100% O2 for 24 h. A significant improvement in oxygenation was observed in apocynin-treated lambs after 24 h of ventilation. Contractility of isolated fifth-generation PA to norepinephrine was attenuated in apocynin-treated lambs. PA constrictions to NO synthase (NOS) inhibition with N-nitro-l-arginine were blunted in PPHN lambs; apocynin restored contractility to N-nitro-l-arginine, suggesting increased NOS activity. Intratracheal apocynin also enhanced PA relaxations to the eNOS activator A-23187 and to the NO donor S-nitrosyl- N-acetyl-penicillamine. Apocynin decreased the interaction between NADPH oxidase subunits p22phox and p47phox and decreased the expression of Nox2 and p22phox in ventilated PPHN lungs. These findings were associated with decreased superoxide and 3-nitrotyrosine levels in the PA of apocynin-treated PPHN lambs. eNOS protein expression, endothelial NO levels, and tetrahydrobiopterin-to-dihydrobiopterin ratios were significantly increased in PA from apocynin-treated lambs, although cGMP levels did not significantly increase and phosphodiesterase-5 activity did not significantly decrease. NADPH oxidase inhibition with apocynin may improve oxygenation, in part, by attenuating ROS-mediated vasoconstriction and by increasing NOS activity.

Decreased association of HSP90 impairs endothelial nitric oxide synthase in fetal lambs with persistent pulmonary hypertension

2003 ◽  
Vol 285 (1) ◽  
pp. H204-H211 ◽  
Author(s):  
Girija G. Konduri ◽  
Jingsong Ou ◽  
Yang Shi ◽  
Kirkwood A. Pritchard
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Ductus Arteriosus ◽  
Pulmonary Arteries ◽  
Heat Shock Protein 90 ◽  
Persistent Pulmonary Hypertension ◽  
Resistance Arteries ◽  
Pulmonary Vasodilation ◽  
No Release ◽  
Endothelial Nitric Oxide

Persistent pulmonary hypertension of newborn (PPHN) is associated with decreased nitric oxide (NO) release and impaired pulmonary vasodilation. We investigated the hypothesis that decreased association of heat shock protein 90 (HSP90) with endothelial NO synthase (eNOS) impairs NO release and vasodilation in PPHN. The responses to the NOS agonist ATP were investigated in fetal lambs with PPHN induced by prenatal ligation of ductus arteriosus, and in sham ligation controls. ATP caused dose-dependent vasodilation in control pulmonary resistance arteries, and this response was attenuated in PPHN vessels. The response of control pulmonary arteries to ATP was attenuated by NG-nitro-l-arginine methyl ester (l-NAME), a NOS antagonist, and geldanamycin, an inhibitor of HSP90-eNOS interaction. The attenuated response to ATP observed in PPHN was improved by pretreatment of vessels with l-NAME or 4,5-dihydroxy-1,3-benzene-disulfonate, a superoxide scavenger. Pulmonary arteries from PPHN lambs had decreased basal levels of HSP90 in association with eNOS. Association of HSP90 with eNOS and NO release increased in response to ATP in control pulmonary artery endothelial cells, but not in cells from PPHN lambs. Decreased HSP90-eNOS interactions may contribute to the impaired NO release and vasodilation observed in the ductal ligation model of PPHN.

Biology of bone marrow-derived endothelial cell precursors

2007 ◽  
Vol 292 (1) ◽  
pp. H1-H18 ◽  
Author(s):  
Gina C. Schatteman ◽  
Martine Dunnwald ◽  
Chunhua Jiao
Keyword(s):  
Bone Marrow ◽  
Endothelial Cell ◽  
Marrow Cell ◽  
Tumor Type ◽  
Physiological Relevance ◽  
Bone Marrow Derived Cells ◽  
And Function ◽  
Endothelial Nitric Oxide ◽  
The Impact ◽  
Endothelial Precursors

Over the past decade, the old idea that the bone marrow contains endothelial cell precursors has become an area of renewed interest. While some still believe that there are no endothelial precursors in the blood, even among those who do, there is no consensus as to what they are or what they do. In this review, we describe the problems in identifying endothelial cells and conclude that expression of endothelial nitric oxide synthase may be the most reliable antigenic indicator of the phenotype. The evidence for two different classes of endothelial precursors is also presented. We suggest that, though there is no single endothelial cell precursor, we may be able to use these phenotypic variations to our advantage in better understanding their biology. We also discuss how a variety of genetic, epigenetic, and methodological differences can account for the seemingly contradictory findings on the physiological relevance of bone marrow-derived precursors in normal vascular maintenance and in response to injury. Data on the impact of tumor type and location on the contribution of bone marrow-derived cells to the tumor vasculature are also presented. These data provide hope that we may ultimately be able to predict those tumors in which bone marrow-derived cells will have a significant contribution and design therapies accordingly. Finally, factors that regulate bone marrow cell recruitment to and function in the endothelium are beginning to be identified, and several of these, including stromal derived factor 1, monocyte chemoattractant factor-1, and vascular endothelial growth factor are discussed.

Trauma induced by nontraumatic coronary devices and its impact on vascular reactivity and morphology

2002 ◽  
Vol 283 (6) ◽  
pp. H2356-H2362 ◽  
Author(s):  
Jörg M. Strotmann ◽  
Johann Bauersachs ◽  
Daniela Fraccarollo ◽  
Michael Kirchengast ◽  
Philipp A. Schnabel ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Vascular Reactivity ◽  
Low Pressure ◽  
Coronary Perfusion ◽  
Neointima Formation ◽  
Clinical Consequences ◽  
The Right ◽  
And Function ◽  
Endothelial Nitric Oxide ◽  
The Impact

This study evaluated the impact of low-pressure balloon devices on coronary morphology and function. An active coronary perfusion catheter (2.5-mm balloon diameter, inflation with 1 bar for 30 min) was placed in the left anterior descending coronary artery of 12 German landrace pigs under general anesthesia. After 3 mo, coronary segments with balloon contact were compared with control segments taken from the right coronary artery as to histology, vascular reactivity, and expression of endothelial nitric oxide synthase. Thirty-three balloon treated segments were analyzed. Twenty of these segments (61%) showed neointima formation. In these segments endothelium-independent relaxation induced by sodium nitroprusside was preserved. However, endothelium-dependent bradykinin-induced relaxation was significantly attenuated compared with both the control segments and the balloon-treated segments without neointima formation. In >60% of the ballooned arterial segments examined, low-pressure balloon devices induced neointima formation accompanied by reduced endothelium-dependent relaxation. Thus interventions with so-called nontraumatic coronary devices can induce relevant vascular injury, with potential adverse clinical consequences.

Estradiol-induced attenuation of pulmonary hypertension is not associated with altered eNOS expression

2001 ◽  
Vol 280 (1) ◽  
pp. L88-L97 ◽  
Author(s):  
Thomas C. Resta ◽  
Nancy L. Kanagy ◽  
Benjimen R. Walker
Keyword(s):  
Pulmonary Hypertension ◽  
Chronic Hypoxia ◽  
Vascular Tissue ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Inhibitory Influence ◽  
Enos Expression ◽  
17Β Estradiol ◽  
Spermine Nonoate ◽  
Endothelial Nitric Oxide

Female rats develop less severe pulmonary hypertension (PH) in response to chronic hypoxia compared with males, thus implicating a potential role for ovarian hormones in mediating this gender difference. Considering that estrogen upregulates endothelial nitric oxide (NO) synthase (eNOS) in systemic vascular tissue, we hypothesized that estrogen inhibits hypoxic PH by increasing eNOS expression and activity. To test this hypothesis, we examined responses to the endothelium-derived NO-dependent dilator ionomycin and the NO donors S-nitroso- N-acetylpenicillamine and spermine NONOate in U-46619-constricted, isolated, saline-perfused lungs from the following groups: 1) normoxic rats with intact ovaries, 2) chronic hypoxic (CH) rats with intact ovaries, 3) CH ovariectomized rats given 17β-estradiol (E2β), and 4) CH ovariectomized rats given vehicle. Additional experiments assessed pulmonary eNOS levels in each group by Western blotting. Our findings indicate that E2β attenuated chronic hypoxia-induced right ventricular hypertrophy, pulmonary arterial remodeling, and polycythemia. Furthermore, although CH augmented vasodilatory responsiveness to ionomycin and increased pulmonary eNOS expression, these responses were not potentiated by E2β. Finally, responses to S-nitroso- N-acetylpenicillamine and spermine NONOate were similarly attenuated in all CH groups compared with normoxic control groups. We conclude that the inhibitory influence of E2β on chronic hypoxia-induced PH is not associated with increased eNOS expression or activity.

scholarly journals Protein complex formation with heat shock protein 90 in chronic hypoxia-induced pulmonary hypertension in newborn piglets

2010 ◽  
Vol 299 (4) ◽  
pp. H1190-H1204 ◽  
Author(s):  
Candice D. Fike ◽  
Sandra L. Pfister ◽  
James C. Slaughter ◽  
Mark R. Kaplowitz ◽  
Yongmei Zhang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Chronic Hypoxia ◽  
Heat Shock Protein 90 ◽  
Resistance Arteries ◽  
Newborn Piglets ◽  
Protein Complex Formation ◽  
Endothelial Nitric Oxide ◽  
The Impact

Aberrant interactions between heat shock protein (Hsp)90 and its client proteins could contribute to pulmonary hypertension. We tested the hypotheses that 1) the interaction between Hsp90 and its known client protein, endothelial nitric oxide synthase (eNOS), is impaired in pulmonary resistance arteries (PRAs) from piglets with pulmonary hypertension caused by exposure to 3 or 10 days of hypoxia and 2) Hsp90 interacts with the prostanoid pathway proteins prostacyclin synthase (PGIS) and/or thromboxane synthase (TXAS). We also determined whether Hsp90 antagonism with geldanamycin alters the agonist-induced synthesis of prostacyclin and thromboxane or alters PRA responses to these prostaglandin metabolites. Compared with normoxic piglets, less eNOS coimmunoprecipitated with Hsp90 in PRAs from hypoxic piglets. Despite reduced Hsp90-eNOS interactions, dilation to ACh was enhanced in geldanamycin-treated PRAs from hypoxic, but not normoxic, piglets. In PRAs from all groups of piglets, PGIS and TXAS coimmunoprecipitated with Hsp90. Geldanamycin reduced the ACh-induced synthesis of prostacyclin and thromboxane and altered responses to the thromboxane mimetic U-46619 in PRAs from all groups. Although geldanamycin enhanced responses to prostacyclin in PRAs from both groups of hypoxic piglets, geldanamycin had no effect on prostacyclin responses in PRAs from either group of normoxic piglets. Our findings indicate that Hsp90 influences both prostanoid and eNOS signaling in the pulmonary circulation of newborn piglets and that the impact of pharmacological inhibition of Hsp90 on these signaling pathways is altered during exposure to chronic hypoxia.

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