Enhancement of Aortic Contractility by Endothelin Following Prolonged Hypoxia in vivo

Zacour, Mary; Toporsian, Mourad; Auer, Grant; Černáček, Peter; Ward, Michael E.

doi:10.1006/pupt.1998.0137

Cited by 8 publications

(7 citation statements)

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“…The EC 50 value was lower (i.e., sensitivity was increased) after endothelial ablation in rings from both normoxic and hypoxic animals. Removal of the endothelium increased the maximum tension during PE-induced contraction in rings from normoxic rats, whereas, as noted previously (14,27), tension was greater in endothelium-intact than -denuded rings from rats exposed to hypoxia. Treatment with l-NAME increased maximum tension and decreased the EC 50 during PE-induced contraction in endothelium-intact rings from both normoxic and hypoxic animals but had no effect on the response to either PE or KCl in endothelium-denuded rings from normoxic rats.…”

Section: Resultssupporting

confidence: 79%

Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant

Ward

Toporsian²,

Scott³

et al. 2005

J. Clin. Invest.

102

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We tested the hypothesis that induction of neuronal NO synthase (nNOS) impairs vascular smooth muscle contractility after hypoxia. nNOS protein was increased in aorta, mesenteric arterioles, pulmonary arteries, brain, and diaphragm from rats exposed to 8% O 2 for 48 hours and in human aortic SMCs after hypoxic incubation (1% O 2 ). Ca 2+ -dependent NO synthase activity was increased in endothelium-denuded aortic segments from hypoxia-exposed rats. N G -nitro-l-arginine methyl ester enhanced the contractile responses of endothelium-denuded aortic rings and mesenteric arterioles from hypoxia-exposed but not normoxic rats (P < 0.05). The hypoxia-inducible mRNA transcript expressed by human cells was found to contain a novel 5′-untranslated region, consistent with activation of transcription in the genomic region contiguous with exon 2. Translational efficiency of this transcript is markedly increased compared with previously described human nNOS mRNAs. Transgenic mice possessing a lacZ reporter construct under control of these genomic sequences demonstrated expression of the construct after exposure to hypoxia (8% O 2 , 48 hours) in the aorta, mesenteric arterioles, renal papilla, and brain. These results reveal a novel human nNOS promoter that confers the ability to rapidly upregulate nNOS expression in response to hypoxia with a functionally significant effect on vascular smooth muscle contraction.

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Section: Resultssupporting

confidence: 79%

Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant

Ward

Toporsian²,

Scott³

et al. 2005

J. Clin. Invest.

102

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“…As reported in a previous study (52), this concentration of BQ-123 completely inhibited the response to ET-1 in rat aorta, with no effect on phenylephrine-induced contraction in endothelium-intact or -denuded aortic rings from normoxic rats or in endothelium-denuded aortic rings from rats exposed to hypoxia.…”

Section: Methodssupporting

confidence: 86%

“…Classically, this would be taken to indicate that NOS-and HO-mediated inhibition of contraction are of approximately equal importance and independent of each other. CO is significantly less potent than NO as an activator of soluble guanylyl cyclase (sGC) (13), however, and may function as a partial sGC agonist (52). Therefore, the effect of HO inhibition may be enhanced under conditions of NO deficiency, and an interaction between these two pathways will be masked by this method of evaluation.…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia is a particularly potent activator of endothelin-1 (ET-1) production (19,47), and recent studies indicate that ET-1 plays a central role in adaptation to hypoxia, regulating peripheral chemoreceptor sensitivity (36) and potentiating the vascular responses that enhance pulmonary gas exchange and tissue oxygen extraction (5,34,48,52). Given the need to balance these important functions with the potential for exacerbation of ischemic injury through excessive vasoconstriction (6), it is not surprising that mechanisms have evolved to modulate the local bioavailability and potency of ET-1 to preserve the relationship between regional oxygen delivery and metabolic demand (20,46).…”

mentioning

confidence: 99%

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Interaction between endothelial heme oxygenase-2 and endothelin-1 in altered aortic reactivity after hypoxia in rats

Govindaraju

Teoh²,

Hamid³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Interaction between endothelial heme oxygenase-2 and endothelin-1 in altered aortic reactivity after hypoxia in rats. Am J Physiol Heart Circ Physiol 288: H962-H970, 2005. First published October 14, 2004; doi:10.1152/ajpheart. 01218.2003.-The aim of this study was to determine whether increased expression of heme oxygenase (HO) contributes to impairment of aortic contractile responses after hypoxia through effects on reactivity to endothelin-1 (ET-1). Thoracic aortas from normoxic rats and rats exposed to hypoxia (10% O2) for 16 or 48 h were mounted in organ bath myographs for contractile studies, fixed in paraformaldehyde, or frozen in liquid nitrogen for protein extraction. In rings from normoxic rats, the HO inhibitor tin protoporphyrin IX (SnPP IX, 10 M) did not alter the response to phenylephrine or ET-1. In rings from rats exposed to 16-h hypoxia, maximum tension generated in response to these agonists was higher in endothelium-intact but not -denuded rings in the presence of SnPP IX. In rings from rats exposed to 48-h hypoxia SnPP IX increased contraction in endothelium-intact but not -denuded rings. In endothelium-intact aortic rings from rats exposed to 16-h hypoxia incubated with endothelin A receptorspecific antagonist BQ-123 (10 Ϫ7 M), SnPP IX did not alter phenylephrine-induced contraction. Aortic ET-1 protein levels, measured by radioimmunoassay, were increased in rats exposed to hypoxia for 16 and 48 h. Western blotting showed that HO-1 and HO-2 protein were increased after 16 h of hypoxia and returned to near-control levels after 48 h. Increase in HO-1 protein was detected in endotheliumintact and -denuded rings. Removal of endothelium abolished the increase in HO-2 immunoreactivity. Immunohistochemistry localized expression of HO-1 protein to vascular smooth muscle, whereas HO-2 was only detected in endothelium. HO-2 is expressed by aortic endothelial cells early during hypoxic exposure and impairs ET-1-mediated potentiation of contraction to ␣-adrenoceptor stimulation. vascular reactivity; oxygen delivery; blood flow regulation THE ENDOTHELINS ARE POTENT vasoconstrictor peptides released by endothelial cells in response to a variety of stimuli. Hypoxia is a particularly potent activator of endothelin-1 (ET-1) production (19,47), and recent studies indicate that ET-1 plays a central role in adaptation to hypoxia, regulating peripheral chemoreceptor sensitivity (36) and potentiating the vascular responses that enhance pulmonary gas exchange and tissue oxygen extraction (5, 34, 48, 52). Given the need to balance these important functions with the potential for exacerbation of ischemic injury through excessive vasoconstriction (6), it is not surprising that mechanisms have evolved to modulate the local bioavailability and potency of ET-1 to preserve the relationship between regional oxygen delivery and metabolic demand (20, 46). Heme oxygenase (HO), the rate-limiting enzyme in the heme catabolic pathway that yields bilirubin as the final product, catalyzes the formation of biliverdin through th...

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“…The compensatory mechanisms that preserve blood flow to vital organs under these conditions are, in part, dependent on the release of endothelium-derived vasoregulatory factors (1)(2)(3). During prolonged exposure to hypoxia, endothelial function is impaired and the adaptive responses that they mediate are compromised (2)(3)(4). Investigation of mechanisms that preserve endothelial cell survival and function in this setting is needed so that therapeutic strategies to mitigate the vascular effects of hypoxia may be developed.…”

mentioning

confidence: 99%

Enhanced Translation of Heme Oxygenase-2 Preserves Human Endothelial Cell Viability during Hypoxia

Ho²,

Gingerich

et al. 2010

Journal of Biological Chemistry

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Heme oxygenases (HOs) -1 and -2 catalyze the breakdown of heme to release carbon monoxide, biliverdin, and ferrous iron, which may preserve cell function during oxidative stress. HO-1 levels decrease in endothelial cells exposed to hypoxia, whereas the effect of hypoxia on HO-2 expression is unknown. The current study was carried out to determine if hypoxia alters HO-2 protein levels in human endothelial cells and whether this enzyme plays a role in preserving their viability during hypoxic stress. Human umbilical vein endothelial cells (HUVECs), human aortic endothelial cells (HAECs), and human blood outgrowth endothelial cells were exposed to 21% or 1% O 2 for 48 or 16 h in the presence or absence of tumor necrosis factor-␣ (10 ng/ml) or H 2 O 2 (100 M). In all three endothelial cell types HO-1 mRNA and protein levels were decreased following hypoxic incubation, whereas HO-2 protein levels were unaltered. In HUVECs HO-2 levels were maintained during hypoxia despite a 57% reduction in steady-state HO-2 mRNA level and a 43% reduction in total protein synthesis. Polysome profiling revealed increased HO-2 transcript association with polysomes during hypoxia consistent with enhanced translation of these transcripts. Importantly, inhibition of HO-2 expression by small interference RNA increased oxidative stress, exacerbated mitochondrial membrane depolarization, and enhanced caspase activation and apoptotic cell death in cells incubated under hypoxic but not normoxic conditions. These data indicate that HO-2 is important in maintaining endothelial viability and may preserve local regulation of vascular tone, thrombosis, and inflammatory responses during reductions in systemic oxygen delivery.

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Enhancement of Aortic Contractility by Endothelin Following Prolonged Hypoxia in vivo

Cited by 8 publications

References 0 publications

Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant

Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant

Interaction between endothelial heme oxygenase-2 and endothelin-1 in altered aortic reactivity after hypoxia in rats

Enhanced Translation of Heme Oxygenase-2 Preserves Human Endothelial Cell Viability during Hypoxia

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