Downregulation of Endothelial Nitric Oxide Synthase in Rat Aorta After Prolonged Hypoxia In Vivo

Toporsian, Mourad; Govindaraju, Karuthapillai; Nagi, Mohammed; Eidelman, David H.; Thibault, Gaétan; Ward, Michael E.

doi:10.1161/01.res.86.6.671

Cited by 76 publications

(63 citation statements)

References 28 publications

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“…This variability probably reflects differences in species and vascular beds, methods used to maintain the cells, and duration and severity of the hypoxic exposures. Our findings of downregulation of eNOS activity and expression in cardiac tissue of hypoxic patients is in agreement with the findings of Toporsian et al 11 These authors showed, in rat aorta in vivo, that hypoxic downregulation of eNOS expression is a relevant mechanism used by endothelium to allow a predominance of substances that enhance vascular contraction through the removal of an inhibitor of vasoconstriction, seeking to redistribute the flow to vital organs in hypoxic conditions. We found, in cardiac tissue, the same relationship as occurred in the rat aorta.…”

Section: Discussionsupporting

confidence: 93%

Influence of Hypoxia on Nitric Oxide Synthase Activity and Gene Expression in Children With Congenital Heart Disease

et al. 2001

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Background-Chronic hypoxia has been shown to modulate nitric oxide (NO) responses in different cell models, but the relationship between hypoxia and NO synthase (NOS) regulation in humans was not studied. We studied the relationship between endothelial and inducible NOS (eNOS and iNOS) activities and expression and chronic hypoxia in children with cyanotic and acyanotic congenital heart defects. Methods and Results-Right atrial tissue was excised from 18 patients during cardiac surgery. eNOS and iNOS activities were measured by conversion of L- [H 3 ]arginine to L-[H 3 ]citrulline. Gene expression of eNOS and iNOS was quantified by competitive reverse transcription-polymerase chain reaction. The eNOS activity and expression were significantly reduced in cyanotic hearts compared with acyanotic hearts: 0.38Ϯ0.14 versus 1.06Ϯ0.11 pmol · mg Ϫ1 · min

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Section: Discussionsupporting

confidence: 93%

Influence of Hypoxia on Nitric Oxide Synthase Activity and Gene Expression in Children With Congenital Heart Disease

et al. 2001

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“…Previous studies have demonstrated that hypoxia causes a decrease in eNOS expression in rat aortas (30). Real time RT-PCR analysis of sONE expression revealed that sONE was induced ϳ2-fold by 16 h of hypoxia and more than 3-fold after 7 days of hypoxia treatment (Fig.…”

Section: Sone Mrna Is Hypoxia-inducible and Is Reciprocallymentioning

confidence: 74%

Hypoxia-inducible Expression of a Natural cis-Antisense Transcript Inhibits Endothelial Nitric-oxide Synthase

Fish

Matouk

Yeboah

et al. 2007

Journal of Biological Chemistry

131

120

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The destabilization of endothelial nitric-oxide synthase (eNOS) mRNA in hypoxic endothelial cells may be important in the etiology of vascular diseases, such as pulmonary hypertension. Recently, an overlapping antisense transcript to eNOS/NOS3 was implicated in the post-transcriptional regulation of eNOS. We demonstrate here that expression of sONE, also known as eNOS antisense (NOS3AS) or autophagy 9-like 2 (APG9L2), is robustly induced by hypoxia or functional deficiency of von Hippel-Lindau protein. sONE is also up-regulated in the aortas of hypoxic rats. In hypoxic endothelial cells, sONE expression negatively correlates with eNOS expression. Blocking the hypoxic induction of sONE by RNA interference attenuates the fall in both eNOS RNA and protein. We provide evidence that the induction of sONE primarily involves transcript stabilization rather than increased transcriptional activity and is von Hippel-Lindau-but not hypoxia-inducible factor 2␣-dependent. We also demonstrate that sONE transcripts are enriched in the nucleus of normoxic cells and that hypoxia promotes an increase in the level of cytoplasmic and polyribosome-associated, sONE mRNA. The finding that eNOS expression can be regulated by an overlapping cis-antisense transcript in a stimulus-dependent fashion provides evidence that sense/antisense interactions may play a previously unappreciated role in vascular disease pathogenesis.

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“…Another plausible mechanism for impaired endothelium-dependent vasodilatation in OSAS is the reduction in eNOS protein, based on the finding that eNOS protein was decreased in the rat aorta under low oxygen tension, 32 and that hypoxia decreases the expression of eNOS mRNA and protein in cultured endothelial cells. 33 In addition, the present result that %FMD increased but plasma ADMA and NOx concentrations were unchanged at 1 week after nCPAP (Fig 1A,C, and D) suggests that FMD starts to improve before ADMA and NOx start to change.…”

Section: Discussionmentioning

confidence: 99%

Amelioration of Vascular Endothelial Dysfunction in Obstructive Sleep Apnea Syndrome by Nasal Continuous Positive Airway Pressure-Possible Involvement of Nitric Oxide and Asymmetric NG, NG-Dimethylarginine-

Ohike

Kozaki

Iijima

et al. 2005

Circ J

143

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ndothelial dysfunction is recognized as an early phase of arteriosclerosis 1 and an important cause of that dysfunction is impaired nitric oxide (NO) release from the endothelium. Endothelial NO is a key regulator of vascular homeostasis; it induces vasorelaxation by generating cyclic GMP in the underlying smooth muscle cells, and prevents monocyte adhesion to the endothelium, platelet activation, and smooth muscle cell proliferation. Hence, impaired NO release from injured endothelial cells is regarded as an initiator and promoter of arteriosclerosis.Endothelial NO is produced when L-arginine is con- February 2005 verted to L-citrulline by the enzyme endothelial nitric oxide synthase (eNOS). Endothelial NOS is inhibited by endogenous inhibitors, NG-monomethyl-L-arginine (L-NMMA) and asymmetric dimethylarginine (ADMA), which are structural analogues of L-arginine. 2,3 Plasma ADMA is eliminated by renal excretion and by degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). 4 Increased plasma concentration of ADMA is associated with hypertension, 5 pulmonary hypertension, 6 hypercholesterolemia, 7,8 carotid intima -media thickening, 9 severe peripheral artery occlusive disease, 10 and the clustering of coronary risk factors. 9 These findings suggest that ADMA is responsible for endothelial dysfunction. Obstructive sleep apnea syndrome (OSAS) has been recently attracting attention as a significant disorder. Frequent apnea/hypopnea attacks followed by arousal results in insufficient sleep at night, causing daytime sleepiness, leading to work inefficiency, and even traffic accidents. In addition, OSAS often accompanies hypertension, obesity, glucose intolerance, and dyslipidemia, all of which are factors in metabolic syndrome. Hence, OSAS is recognized as a risk factor for cardiovascular disease. 11-14 It has been Background Asymmetric NG,NG-dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase and its plasma concentration is elevated in patients with cardiovascular risk factors, including hyperlipidemia, hypertension, diabetes, and hyperhomocysteinemia. Obstructive sleep apnea syndrome (OSAS) has been attracting attention as a risk factor for cardiovascular disorders because it often accompanies hypertension, obesity, glucose impairment, and dyslipidemia, all of which are factors in metabolic syndrome and risk factors for cardiovascular disease. Methods and ResultsIn the present study, flow-mediated vasodilatation (FMD) of the brachial artery and plasma concentrations of ADMA were measured before and after nasal continuous positive airway pressure (nCPAP) therapy, which abrogates apnea, in 10 male patients aged 36-69 years old, who were given a diagnosis of OSAS by polysomnography. The percent FMD (%FMD) improved significantly from 3.3±0.3% to 5.8±0.4% (p<0.01) and 6.6±0.3% (p<0.01), before, 1 week, and 4 weeks after nCPAP, respectively. At the same time, the plasma NOx concentrations, metabolites of NO, tended to increase, bu...

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Downregulation of Endothelial Nitric Oxide Synthase in Rat Aorta After Prolonged Hypoxia In Vivo

Cited by 76 publications

References 28 publications

Influence of Hypoxia on Nitric Oxide Synthase Activity and Gene Expression in Children With Congenital Heart Disease

Influence of Hypoxia on Nitric Oxide Synthase Activity and Gene Expression in Children With Congenital Heart Disease

Hypoxia-inducible Expression of a Natural cis-Antisense Transcript Inhibits Endothelial Nitric-oxide Synthase

Amelioration of Vascular Endothelial Dysfunction in Obstructive Sleep Apnea Syndrome by Nasal Continuous Positive Airway Pressure-Possible Involvement of Nitric Oxide and Asymmetric NG, NG-Dimethylarginine-

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