scholarly journals Histone deacetylase 1 reduces NO production in endothelial cells via lysine deacetylation of NO synthase 3

2014 ◽  
Vol 307 (5) ◽  
pp. H803-H809 ◽  
Author(s):  
Kelly A. Hyndman ◽  
Dao H. Ho ◽  
Martiana F. Sega ◽  
Jennifer S. Pollock
Keyword(s):  
Endothelial Cells ◽  
Histone Deacetylases ◽  
Production Control ◽  
No Synthase ◽  
No Production ◽  
Lysine Acetylation ◽  
Nonhistone Proteins ◽  
Endothelin 1 ◽  
Histone Deacetylase 1 ◽  
Nitrite Production

The lysine acetylation state of nonhistone proteins may be regulated through histone deacetylases (HDACs). Evidence suggests that nitric oxide (NO) synthase 3 (NOS3; endothelial NOS) is posttranslationally lysine acetylated, leading to increased NO production in the endothelium. We tested the hypothesis that NOS3 is lysine acetylated and that upregulated HDAC1-mediated deacetylation leads to reduced NO production in endothelial cells. We determined that NOS3 is basally lysine acetylated in cultured bovine aortic endothelial cells (BAECs). In BAECs, HDAC1 is expressed in the nucleus and cytosol and forms a novel protein-protein interaction with NOS3. Overexpression of HDAC1 in BAECs resulted in a significant reduction in NOS3 lysine acetylation (control = 1.0 ± 0.1 and HDAC1 = 0.59 ± 0.08 arbitrary units, P < 0.01) and significantly blunted basal nitrite production (control 287.7 ± 29.1 and HDAC1 172.4 ± 31.7 pmol·mg−1·h−1, P < 0.05) as well as attenuating endothelin-1-stimulated nitrite production (control = 481.8 ± 50.3 and HDAC1 243.1 ± 48.2 pmol·mg−1·h−1, P < 0.05). While HDAC1 knockdown with small-interfering RNA resulted in no change in NOS3 acetylation level, yet increased basal nitrite production (730.6 ± 99.1 pmol·mg−1·h−1) and further exaggerated increases in endothelin-1 stimulated nitrite production (1276.9 ± 288.2 pmol·mg−1·h−1) was observed. Moreover, overexpression or knockdown of HDAC1 resulted in no significant effect on NOS3 protein expression or NOS3 phosphorylation sites T497, S635, or S1179. Thus these data indicate that upregulated HDAC1 decreases NOS3 activity, most likely through direct lysine deacetylation of NOS3. We propose that HDAC1-mediated deacetylation of NOS3 may represent a novel target for endothelial dysfunction.

Abstract 141: Histone Deacetylase 1 Regulates Nitric Oxide Production and Nitric Oxide Synthase-3 Acetylation in Endothelial Cells

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Kelly A Hyndman ◽  
Dao H Ho ◽  
Jennifer S Pollock
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Histone Deacetylase ◽  
Life Stress ◽  
Trichostatin A ◽  
Early Life Stress ◽  
No Production ◽  
Histone Deacetylase 1 ◽  
Nitrite Production

Previous reports showed that NOS3 is regulated by acetylation through transcriptional mechanisms via histone acetylation or through direct lysine acetylation. Histone deacetylase (HDAC) enzymes and histone acetyltransferases (HATs) modulate acetylation processes. Recent work by our lab, demonstrated increased expression of aortic HDAC1 and HDAC6 while HATs were unchanged in a mouse model of early life stress with endothelial dysfunction. These data suggest a negative correlation between endothelial dysfunction and HDAC expression. The purpose of this study was to test the hypothesis that HDAC1 and 6 regulate endothelial NO production and/or NOS3 acetylation. Initial immunoprecipitation studies with anti-acetyl lysine and anti-NOS3 antibodies demonstrated that NOS3 is basally acetylated in primary bovine aortic endothelial cells (BAECs). Treatment with the HDAC inhibitor, trichostatin A (500 nM) for 1 hr, significantly increased NOS3 acetylation. BAECs were transfected with HDAC1, HDAC6, vector expression plasmids, or untransfected, with nitrite production determined by HPLC and NOS3 acetylation and expression probed by immunoprecipitation and Western blotting. Untransfected and vector transfected control BAECs had similar NO production (357 ± 10 and 344 ± 30 pmol/mg pr/h, respectively, N=6) as well as NOS3 acetylation (7.8 ± 1.6 and 6.8 ±0.3 AU, N=3). HDAC6 transfected BAECs had similar NO production to the control BAECs (272 ± 93 pmol/mg pr/h, N=3) with an increase in NOS3 acetylation (17.4 ± 1.7 AU, N=3). In contrast, HDAC1 overexpression significantly decreased NO production (89 ± 50 pmol/mg pr/h, P< 0.05, N=3) and reduced NOS3 acetylation (3.8 ± 0.5 A.U, N=3), P <0.05). Control transfections, HDAC6, and HDAC1 transfected BAECS all had similar NOS3 expression (10.14 ± 1.8; 9.8 ±1.6; 8.9 ± 1.5; 10.6 ± 1.0 AU, respectively, N=3). Thus, we conclude that HDAC1 regulates NO production via direct lysine deacetylation of NOS3.

Arginase inhibition increases nitric oxide production in bovine pulmonary arterial endothelial cells

2004 ◽  
Vol 287 (1) ◽  
pp. L60-L68 ◽  
Author(s):  
Louis G. Chicoine ◽  
Michael L. Paffett ◽  
Tamara L. Young ◽  
Leif D. Nelin
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
No Synthase ◽  
No Production ◽  
Urea Production ◽  
Pulmonary Arterial ◽  
Factor Α ◽  
Arterial Endothelial Cells ◽  
Regular Medium ◽  
Necrosis Factor

Nitric oxide (NO) is produced by NO synthase (NOS) from l-arginine (l-Arg). Alternatively, l-Arg can be metabolized by arginase to produce l-ornithine and urea. Arginase (AR) exists in two isoforms, ARI and ARII. We hypothesized that inhibiting AR with l-valine (l-Val) would increase NO production in bovine pulmonary arterial endothelial cells (bPAEC). bPAEC were grown to confluence in either regular medium (EGM; control) or EGM with lipopolysaccharide and tumor necrosis factor-α (L/T) added. Treatment of bPAEC with L/T resulted in greater ARI protein expression and ARII mRNA expression than in control bPAEC. Addition of l-Val to the medium led to a concentration-dependent decrease in urea production and a concentration-dependent increase in NO production in both control and L/T-treated bPAEC. In a second set of experiments, control and L/T bPAEC were grown in EGM, EGM with 30 mM l-Val, EGM with 10 mM l-Arg, or EGM with both 10 mM l-Arg and 30 mM l-Val. In both control and L/T bPAEC, treatment with l-Val decreased urea production and increased NO production. Treatment with l-Arg increased both urea and NO production. The addition of the combination l-Arg and l-Val decreased urea production compared with the addition of l-Arg alone and increased NO production compared with l-Val alone. These data suggest that competition for intracellular l-Arg by AR may be involved in the regulation of NOS activity in control bPAEC and in response to L/T treatment.

Regulation of Ca(2+)-dependent nitric oxide synthase in bovine aortic endothelial cells

1995 ◽  
Vol 269 (3) ◽  
pp. C757-C765 ◽  
Author(s):  
B. J. Buckley ◽  
Z. Mirza ◽  
A. R. Whorton
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
No Synthase ◽  
No Production ◽  
Intact Cells ◽  
Aortic Endothelial Cells ◽  
A 23187 ◽  
Transient Rise ◽  
Synthase Inhibitor ◽  
Sustained Increase

Vascular endothelium responds to Ca(2+)-mobilizing agonists by producing nitric oxide (NO), a potent vasodilator and inhibitor of platelet aggregation. Regulation of constitutively expressed endothelial NO synthase (eNOS) in intact cells is not well understood. We investigated the kinetics of NO formation in response to Ca(2+)-mobilizing agonists, the requirement for extracellular L-arginine, and the role of NO in regulating eNOS activity. When endothelial cells were stimulated with bradykinin and ATP in the presence of 100 microM L-arginine, we observed a rapid and transient rise in intracellular Ca2+ concentration ([Ca2+]i) from 50 +/- 8 nM to 698 +/- 74 and 637 +/- 53 nM, respectively, and a rapid and transient rise in NO production from a basal level of 37 pmol.min-1.mg protein-1 to 256 and 275 pmol.min-1.mg protein-1, respectively. When cells were stimulated with A-23187 or thapsigargin in the presence of 100 microM L-arginine, we observed a sustained increase in [Ca2+]i and a sustained increase in NO production. The rate of NO synthesis was linear over 30 min, rising above control levels of 7 pmol/min to 53 pmol/min for A-23187 and 62 pmol/min for thapsigargin. Thapsigargin stimulated NO production and [Ca2+]i with 50% effective concentration values of 0.01 and 0.05 microM, respectively. Ca(2+)-stimulated NO production was attenuated by the NO synthase inhibitor NG-monomethyl-L-arginine, the removal of extracellular L-arginine, and the Ca(2+)-chelator ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. When we exposed cells to NO gas (3.1 mM for 15 min) and S-nitrosoglutathione (10 mM for 1 h) thapsigargin-stimulated NO production was decreased by 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

Endostatin uncouples NO and Ca2+response to bradykinin through enhanced O2−· production in the intact coronary endothelium

2005 ◽  
Vol 288 (2) ◽  
pp. H686-H694 ◽  
Author(s):  
Andrew Y. Zhang ◽  
Eric G. Teggatz ◽  
Ai-Ping Zou ◽  
William B. Campbell ◽  
Pin-Lan Li
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
High Speed ◽  
Imaging Techniques ◽  
No Synthase ◽  
No Production ◽  
Intracellular Ca ◽  
Coronary Endothelial Cells ◽  
Coronary Endothelium ◽  
O2 Production

The present study tested the hypothesis that endostatin stimulates superoxide (O2−·) production through a ceramide-mediating signaling pathway and thereby results in an uncoupling of bradykinin (BK)-induced increases in intracellular Ca2+concentration ([Ca2+]i) from nitric oxide (NO) production in coronary endothelial cells. With the use of high-speed, wavelength-switching, fluorescence-imaging techniques, the [Ca2+]iand NO levels were simultaneously monitored in the intact endothelium of freshly isolated bovine coronary arteries. Under control conditions, BK was found to increase NO production and [Ca2+]iin parallel. When the arteries were pretreated with 100 nM human recombinant endostatin for 1 h, this BK-induced NO production was reduced by 89%, whereas [Ca2+]iwas unchanged. With the conversion rate of l-[3H]arginine to l-[3H]citrulline measured, endostatin had no effect on endothelial NO synthase (NOS) activity, but it stimulated ceramide by activation of sphingomyelinase (SMase), whereby O2−· production was enhanced in endothelial cells. O2−· scavenging by tiron and inhibition of NAD(P)H oxidase by apocynin markedly reversed the effect of endostatin on the NO response to BK. These results indicate that endostatin increases intracellular ceramide levels, which enhances O2−· production through activation of NAD(P)H oxidase. This ceramide-O2−· signaling pathway may contribute importantly to endostatin-induced endothelial dysfunction.

Induction of NO synthase in rat cardiac microvascular endothelial cells by IL-1 beta and IFN-gamma

1995 ◽  
Vol 268 (3) ◽  
pp. H1293-H1303 ◽  
Author(s):  
J. L. Balligand ◽  
D. Ungureanu-Longrois ◽  
W. W. Simmons ◽  
L. Kobzik ◽  
C. J. Lowenstein ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Interleukin 1 ◽  
No Synthase ◽  
Microvascular Endothelial Cells ◽  
Inos Mrna ◽  
Microvascular Endothelium ◽  
Ifn Gamma ◽  
Nitrite Production ◽  
Microvascular Endothelial ◽  
Cardiac Microvascular Endothelial Cells

There are important phenotypic differences between endothelial cells of large vessels and the microvasculature and among microvascular endothelial cells isolated from different tissues and organs. In contrast to most macrovascular endothelial cells, we demonstrate that cultured cardiac microvascular endothelial cells (CMEC) have no detectable constitutive NO synthase (NOS) activity but have a robust increase in NOS activity in response to specific inflammatory cytokines. To determine the identity of the inducible NOS (iNOS) isoform(s) induced by cytokines, we used reverse-transcription polymerase chain reaction techniques to clone and sequence a 217-bp cDNA fragment from CMEC cultures pretreated with interleukin-1 beta (IL-1 beta) and interferon-gamma (IFN-gamma) that was identical to the corresponding portion of the murine macrophage iNOS cDNA. By use of this CMEC iNOS cDNA as a probe in Northern analyses, IL-1 beta, but not IFN-gamma, increased iNOS mRNA content in CMEC, although IFN-gamma markedly potentiated iNOS induction in these cells. In IL-1 beta- and IFN-gamma-pretreated CMEC, dexamethasone only minimally suppressed the rise in iNOS mRNA, protein abundance, or maximal iNOS enzyme activity in whole cell lysates but suppressed nitrite production by 60% in intact CMEC. Dual labeling of cytokine-pretreated CMEC in primary culture with an anti-iNOS antiserum and a fluorescein-labeled lectin specific for the microvascular endothelium of rat heart (GS-1) confirmed the presence of iNOS expression in these cells. iNOS was also detected in microvascular endothelium in situ in ventricular muscle from lipopolysaccharide-, but not sham-injected, rat hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II stimulates the production of NO and peroxynitrite in endothelial cells

1998 ◽  
Vol 274 (1) ◽  
pp. C214-C220 ◽  
Author(s):  
Maria E. Pueyo ◽  
Jean-François Arnal ◽  
Jacques Rami ◽  
Jean-Baptiste Michel
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
No Synthase ◽  
No Production ◽  
Ang Ii ◽  
Calmodulin Antagonist ◽  
Enhanced Chemiluminescence

Angiotensin II (ANG II) produces vasoconstriction by a direct action on smooth muscle cells via AT1 receptors. These receptors are also present in the endothelium, but their function is poorly understood. This study was therefore undertaken to determine whether ANG II elicits the release of nitric oxide (NO) from cultured rat aortic endothelial cells. NO production, measured by the accumulation of nitrite and nitrate, was enhanced by 10−7 M ANG II. The biological activity of the NO released by ANG II action was evaluated by measuring its guanylate cyclase-stimulating activity in smooth muscle cells. The guanosine 3′,5′-cyclic monophosphate (cGMP) content of smooth muscle cells was significantly increased by exposure of supernatant from ANG II-stimulated endothelial cells. These effects resulted from the activation of NO synthase, as they were inhibited by the l-arginine analogs. These ANG II actions were mediated by the AT1 receptor, as shown by their inhibition by the AT1 antagonist losartan. The cGMP production by reporter cells was inhibited by the calmodulin antagonist W-7, suggesting that ANG II activates endothelial calmodulin-dependent NO synthase. This hypothesis is also supported by the increase of intracellular free calcium induced by ANG II in endothelial cells. ANG II also stimulated luminol-enhanced chemiluminescence in endothelial cells. This effect was inhibited by N ω-monomethyl-l-arginine and superoxide dismutase, suggesting that this luminol-enhanced chemiluminescence reflected an increase in peroxynitrite production. Thus ANG II stimulates NO release from macrovascular endothelium, which may modulate the direct vasoconstrictor effect of ANG II on smooth muscle cells. However, this beneficial effect may be counteracted by the simultaneous production of peroxynitrite, which could contribute to several pathological processes in the vascular wall.

Role of calcium and calmodulin in flow-induced nitric oxide production in endothelial cells

1994 ◽  
Vol 266 (3) ◽  
pp. C628-C636 ◽  
Author(s):  
M. J. Kuchan ◽  
J. A. Frangos
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
No Synthase ◽  
Rate Of Change ◽  
No Production ◽  
Rapid Production ◽  
Nos Inhibitor ◽  
Elevated Rate ◽  
Stimulation Of

These experiments demonstrate that exposure of cultured endothelial cells (EC) to well-defined laminar fluid flow results in an elevated rate of NO production. NO production was monitored by release of NOx (NO2- + NO3(2-) and by cellular guanosine 3',5'-cyclic monophosphate (cGMP) concentration. NO synthase (NOS) inhibitor blocked the flow-mediated stimulation of both NOx and cGMP, indicating that both measurements reflect NO production. Exposure to laminar flow increased NO release in a biphasic manner, with an initial rapid production consequent to the onset of flow followed by a less rapid, sustained production. A similar rapid increase in NO production resulted from an increase in flow above a preexisting level. The rapid initial production of NO was not dependent on shear stress within a physiological range (6-25 dyn/cm2) but may be dependent on the rate of change in shear stress. The sustained release of NO was dependent on physiological levels of shear stress. The calcium (Ca2+) or calmodulin (CaM) dependence of the initial and sustained production of NO was compared with bradykinin (BK)-mediated NO production. Both BK and the initial production were inhibited by Ca2+ and CaM antagonists. In contrast, the sustained shear stress-mediated NO production was not affected, despite the continued functional presence of the antagonists. Dexamethasone had no effect on either the initial or the sustained shear stress-mediated NO production. An inducible NOS does not, therefore, explain the apparent Ca2+/CaM independence of the sustained shear stress-mediated NO production.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Thaliporphine selectively inhibits expression of the inducible, but not the constitutive, nitric oxide synthase

1994 ◽  
Vol 303 (1) ◽  
pp. 289-294 ◽  
Author(s):  
S M Yu
Keyword(s):  
Endothelial Cells ◽  
Interleukin 1 ◽  
No Synthase ◽  
Nitrite Accumulation ◽  
Necrosis Factor Alpha ◽  
Inducible No Synthase ◽  
Nitrite Production ◽  
Anaesthetized Rats ◽  
Vascular Hyporeactivity ◽  
Constitutive Nitric Oxide Synthase

Formation of nitrites/nitrates caused by lipopolysaccharide (LPS) in J774.2 macrophages was inhibited by thaliporphine, an aporphine derivative isolated from the plant Neolitsea konishii K. This inhibition of nitrite synthesis in LPS-stimulated macrophages by thaliporphine was similar to that by cycloheximide, NG-methyl-L-arginine (MeArg) and dexamethasone. Thaliporphine, but not MeArg, inhibited expression of inducible NO synthase without directly affecting enzyme activity. However, thaliporphine did not inhibit nitrite production by NO synthase that had already been induced by prior exposure to LPS for which any possible further induction was inhibited by cycloheximide. In endothelial cells, nitrite formation induced by bradykinin (in the presence of 0.2 mM Ca2+) was inhibited by MeArg. However, incubation of endothelial cells with dexamethasone, cycloheximide and thaliporphine did not affect this Ca(2+)-dependent nitrite production. Thaliporphine (0.1-100 microM) dose-dependently inhibited nitrite accumulation in macrophages stimulated by interleukin-1 beta (IL-1 beta) whereas nitrite formation induced by tumour necrosis factor alpha was not inhibited. LPS-stimulated IL-1 beta synthesis in macrophages was significantly inhibited by thaliporphine, but thaliporphine had only minimal effect on LPS-stimulated IL-1 beta synthesis in endothelial cells. These results demonstrate that thaliporphine inhibits LPS induction of NO synthase expression, and that the mechanism of action of thaliporphine is via inhibition of LPS-stimulated IL-1 beta synthesis in macrophages. In anaesthetized rats subjected to LPS, pretreatment with thaliporphine partially restored the fall in mean arterial pressure and the vascular hyporeactivity to noradrenaline 3 h after LPS injection. In conclusion, thaliporphine selectively inhibited expression of inducible NO synthase, and may thus hold potential for the treatment of endotoxaemia.

Glutamine metabolism to glucosamine is necessary for glutamine inhibition of endothelial nitric oxide synthesis

2001 ◽  
Vol 353 (2) ◽  
pp. 245-252 ◽  
Author(s):  
Guoyao WU ◽  
Tony E. HAYNES ◽  
Hui LI ◽  
Wene YAN ◽  
Cynthia J. MEININGER
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
No Synthase ◽  
Glutamine Metabolism ◽  
No Production ◽  
Nitric Oxide Synthesis ◽  
Inhibiting Effect ◽  
Arginine Transport ◽  
Metabolic Basis ◽  
Endothelial Nitric Oxide

L-Glutamine is a physiological inhibitor of endothelial NO synthesis. The present study was conducted to test the hypothesis that metabolism of glutamine to glucosamine is necessary for glutamine inhibition of endothelial NO generation. Bovine venular endothelial cells were cultured for 24h in the presence of 0, 0.1, 0.5 or 2mM D-glucosamine, or of 0.2 or 2mM L-glutamine with or without 20µM 6-diazo-5-oxo-L-norleucine (DON) or with 100µM azaserine. Both DON and azaserine are inhibitors of L-glutamine:D-fructose-6-phosphate transaminase (isomerizing) (EC 2.6.1.16), the first and rate controlling enzyme in glucosamine synthesis. Glucosamine at 0.1, 0.5 and 2mM decreased NO production by 34, 45 and 56% respectively compared with controls where glucosamine was lacking. DON (20µM) and azaserine (100µM) blocked glucosamine synthesis and prevented the inhibition of NO generation by glutamine. Neither glutamine nor glucosamine had an effect on NO synthase (NOS) activity, arginine transport or cellular tetrahydrobiopterin and Ca2+ levels. However, both glutamine and glucosamine inhibited pentose cycle activity and decreased cellular NADPH concentrations; these effects of glutamine were abolished by DON or azaserine. Restoration of cellular NADPH levels by the addition of 1mM citrate also prevented the inhibiting effect of glutamine or glucosamine on NO synthesis. A further increase in cellular NADPH levels by the addition of 5mM citrate resulted in greater production of NO. Collectively, our results demonstrate that the metabolism of glutamine to glucosamine is necessary for the inhibition of endothelial NO generation by glutamine. Glucosamine reduces the cellular availability of NADPH (an essential cofactor for NOS) by inhibiting pentose cycle activity, and this may be a metabolic basis for the inhibition of endothelial NO synthesis by glucosamine.

Hypoxia decreases endothelin-1 synthesis by rat lung endothelial cells

1995 ◽  
Vol 269 (2) ◽  
pp. L215-L220 ◽  
Author(s):  
B. A. Markewitz ◽  
D. E. Kohan ◽  
J. R. Michael
Keyword(s):  
Endothelial Cells ◽  
Polymerase Chain Reaction Amplification ◽  
Inhibitory Effect ◽  
Airway Smooth Muscle Cells ◽  
No Production ◽  
Rat Lung ◽  
Rnase Protection ◽  
Endothelin 1 ◽  
Hypoxic Environment ◽  
Lung Endothelial Cells

Endothelin-1 (ET-1) is a 21-amino acid peptide synthesized by several cell types in the lung. Locally, ET-1 regulates vascular and airway tone and is mitogenic for vascular and airway smooth muscle cells. Little, however, is known about the regulation of ET-1 in pulmonary endothelial cells. Cultured rat lung endothelial cells (RLECs) release significant amounts of ET-1 into the supernatant, and isolation of RNA followed by reverse transcription and polymerase chain reaction amplification confirms the presence of ET-1 mRNA. Exposure of RLECs to a hypoxic environment for 24 h decreases ET-1 production by approximately 50% compared with normoxic controls. The effect of hypoxia is reversible upon restoration of a normoxic environment. RNase protection studies reveal decreased ET-1 mRNA in hypoxic cells. Inhibition of nitric oxide (NO) synthase increases ET-1 synthesis during normoxia and hypoxia without altering the inhibitory effect of hypoxia. The addition of 10% carbon monoxide (CO) to the hypoxic environment does not erase the effect of hypoxia on ET-1 production, suggesting that the transduction process does not involve a heme sensor. In summary, we conclude that 1) RLECs synthesize ET-1; 2) hypoxia reversibly decreases ET-1 production; 3) constitutive NO production decreases ET-1 release during normoxia and hypoxia; 4) inhibiting constitutive NO synthesis does not prevent the decrease in ET-1 release caused by hypoxia; and 5) this effect of hypoxia appears to be transduced without the involvement of a heme sensor.

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