Nitric oxide contributes to 20-HETE-induced relaxation of pulmonary arteries

Yu, Ming Chih; McAndrew, R.P.; Al-Saghir, Rula; Maier, Kristopher G.; Medhora, Meetha; Roman, Richard J.; Jacobs, Elizabeth R.

doi:10.1152/japplphysiol.00247.2002

Cited by 38 publications

(49 citation statements)

References 32 publications

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“…Birks et al (9) have shown that isolated human pulmonary arteries dilate in a dose-dependent fashion to 20-HETE and that microsomes from adult lung have the enzymatic capacity to synthesize 20-HETE from arachidonic acid. 20-HETE relaxes preconstricted isolated rabbit and bovine pulmonary artery rings (34,35). Moreover, inhibition of endogenous 20-HETE release results in increased basal PAP and enhanced vasoconstrictor responses to hypoxia in isolated perfused rabbit lungs, suggesting that release of 20-HETE serves to maintain the low baseline PVR that characterizes the adult lung (35).…”

Section: Discussionmentioning

confidence: 96%

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Inhibition of 20-HETE abolishes the myogenic response during NOS antagonism in the ovine fetal pulmonary circulation

Parker¹,

Grover²,

Kinsella³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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anisms that maintain high pulmonary vascular resistance (PVR) and oppose vasodilation in the fetal lung are poorly understood. In fetal lambs, increased pulmonary artery pressure evokes a potent vasoconstriction, suggesting that a myogenic response contributes to high PVR in the fetus. In adult systemic circulations, the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been shown to modulate the myogenic response, but its role in the fetal lung is unknown. We hypothesized that acute increases in pulmonary artery pressure release 20-HETE, which causes vasoconstriction, or a myogenic response, in the fetal lung. To address this hypothesis, we studied the hemodynamic effects of , a specific inhibitor of 20-HETE production, on the pulmonary vasoconstriction caused by acute compression of the ductus arteriosus (DA) in chronically prepared fetal sheep. An inflatable vascular occluder around the DA was used to increase pulmonary artery pressure under three study conditions: control, after pretreatment with nitro-L-arginine (L-NA; to inhibit shear-stress vasodilation), and after combined treatment with both L-NA and a specific 20-HETE inhibitor, DDMS. We found that DA compression after L-NA treatment increased PVR by 44 Ϯ 12%. Although intrapulmonary DDMS infusion did not affect basal PVR, DDMS completely abolished the vasoconstrictor response to DA compression in the presence of L-NA (44 Ϯ 12% vs. 2 Ϯ 4% change in PVR, L-NA vs. L-NA ϩ DDMS, P Ͻ 0.05). We conclude that 20-HETE mediates the myogenic response in the fetal pulmonary circulation and speculate that pharmacological inhibition of 20-HETE might have a therapeutic role in neonatal conditions characterized by pulmonary hypertension. fetus; N-methylsufonyl-12,12-dibromododec-11-enamide; ductus arteriosus; 20-hydroxyeicosatetraenoic acid; nitric oxide synthase HIGH PULMONARY VASCULAR RESISTANCE (PVR) characterizes the fetal lung, resulting in very low pulmonary blood flow compared with the newborn or adult. At birth, in response to the release of several vasoactive agents, the lung undergoes a marked vasodilation, and pulmonary blood flow increases dramatically (2,11,14,31). The sustained nature of that vasodilator response stands in marked contrast to the fetal pulmonary circulation. Although the fetal lung is capable of vasodilating to a number of stimuli, including increased oxygen tension, alkalosis, and shear stress (1,3,(12)(13)(14)23), past studies have demonstrated that the vasodilator response is time limited. Despite ongoing exposure to the dilator stimulus, pulmonary blood flow gradually returns to normal, preserving the fetal phenotype marked by high PVR (1, 4).Our group (1, 28) recently reported that compression of the ductus arteriosus (DA) in the fetus, which diverts blood flow into the lung and simultaneously increases shear stress and pulmonary artery pressure (PAP), causes a biphasic response. Initially, PVR falls in response to increased shear stress. However, over 30 -60 min, a vasoconstrictor response to the increased i...

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Section: Discussionmentioning

confidence: 96%

“…20-HETE causes concentration-dependent relaxation of isolated human adult pulmonary arteries and of adult rabbit pulmonary artery rings (9,21,34). However, in contrast to the fetal lung, myogenic vasoconstriction is not believed to be present in the low-resistance adult pulmonary circulation.…”

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confidence: 99%

Inhibition of 20-HETE abolishes the myogenic response during NOS antagonism in the ovine fetal pulmonary circulation

Parker¹,

Grover²,

Kinsella³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Despite these caveats, these data provide critical links of 20-HETE-induced NO release from BPAECs (36).…”

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confidence: 91%

“…Superoxide is rapidly dismutated to hydrogen peroxide, which then mediates activation of PI3-kinase/Akt, phosphorylation of eNOS, and enhanced release of NO from eNOS in response to 20-HETE in BPAECs. pulmonary endothelium; superoxide; hydrogen peroxide; endothelial nitric oxide synthase WE HAVE PREVIOUSLY DEMONSTRATED that 20-HETE, a product of arachidonic acid catalyzed by CYP4, induces activation of nitric oxide synthase (NOS) from pulmonary artery endothelial cells in a [Ca 2ϩ ] i -dependent manner (9,23,36). Furthermore, 20-HETE releases NO, which contributes to endotheliumdependent vasodilation in pulmonary arteries (9, 19).…”

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confidence: 99%

20-HETE-induced nitric oxide production in pulmonary artery endothelial cells is mediated by NADPH oxidase, H₂O₂, and PI3-kinase/Akt

Bodiga

Gruenloh

Gao

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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. 20-HETE-induced nitric oxide production in pulmonary artery endothelial cells is mediated by NADPH oxidase, H2O2, and PI3-kinase/Akt. Am J Physiol Lung Cell Mol Physiol 298: L564 -L574, 2010. First published January 8, 2010 doi:10.1152/ajplung.00298.2009We have shown that 20-hydroxyeicosatetraenoic acid (20-HETE) increases both superoxide and nitric oxide (NO) production in bovine pulmonary artery endothelial cells (BPAECs). The current study was designed to determine mechanisms underlying 20-HETE-stimulated NO release, and particularly the role of NADPH oxidase, reactive oxygen species, and PI3-kinase in stimulated NO release. Intracellular hydrogen peroxide (H2O2) and NO production were detected by dichlorofluorescein or dihydrorhodamine and diaminofluorescein fluorescence, respectively. Activation of endothelial nitric oxide synthase (eNOS) (Ser1179) and Akt (Ser473) was assessed by comparing the ratio of phosphorylated to total protein expression by Western blotting. Addition of 20-HETE to BPAECs caused an increase in superoxide and hydrogen peroxide, but not peroxynitrite. 20-HETE-evoked activation of Akt and eNOS, as well as enhanced NO release, are dependent on H2O2 as opposed to superoxide in that these endpoints are blocked by PEG-catalase and not PEG-superoxide dismutase. Similarly, 20-HETE-stimulated NO production in BPAECs is blocked by NADPH oxidase inhibitors apocynin or gp91 blocking peptide, and by PI3-kinase/Akt blockers wortmannin, LY-294002, or Akt inhibitor, implicating NADPH oxidase, PI3-kinase, and Akt signaling pathways, respectively, in this process. Together, these data suggest the following scheme: 20-HETE stimulates NADPH oxidase-dependent formation of superoxide. Superoxide is rapidly dismutated to hydrogen peroxide, which then mediates activation of PI3-kinase/Akt, phosphorylation of eNOS, and enhanced release of NO from eNOS in response to 20-HETE in BPAECs. pulmonary endothelium; superoxide; hydrogen peroxide; endothelial nitric oxide synthase WE HAVE PREVIOUSLY DEMONSTRATED that 20-HETE, a product of arachidonic acid catalyzed by CYP4, induces activation of nitric oxide synthase (NOS) from pulmonary artery endothelial cells in a [Ca 2ϩ ] i -dependent manner (9,23,36). Furthermore, 20-HETE releases NO, which contributes to endotheliumdependent vasodilation in pulmonary arteries (9, 19). Growing evidence from our own work as well as that from others indicates that 20-HETE activates the vascular NADPH oxidase, leading to increased production of superoxide anion (O 2•Ϫ ) and hydrogen peroxide (2,23,32 /calmodulin-dependent protein kinase II/Janus-kinase 2-dependent pathway in bovine aortic endothelial cells (6, 12). Furthermore, it has been shown that exogenous H 2 O 2 in micromolar concentrations activates eNOS from porcine aortic endothelial cells to cause endothelial NO release (7,28). Superoxide may also react with NO in a diffusion-limited fashion to form peroxynitrite. This species is believed to result in the loss of many of the beneficial effects of NO, including vasodila...

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“…However, this molecule is formed by the same pathway as leukotrienes, and shares structural similarities with both EETs and 20-HETE all of which are known for their ability to modulate vascular (34,40) and airway smooth muscle tone (3,6,36) in asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome patients. Alteration of bronchial wall reactivity to various eicosanoids and cytokines is a characteristic feature of chronic asthma.…”

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confidence: 99%

5-Oxo-ETE regulates tone of guinea pig airway smooth muscle via activation of Ca²⁺pools and Rho-kinase pathway

Mercier¹,

Morin²,

Cloutier³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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. 5-Oxo-ETE regulates tone of guinea pig airway smooth muscle via activation of Ca 2ϩ pools and Rho-kinase pathway. Am J Physiol Lung Cell Mol Physiol 287: L631-L640, 2004. First published April 16, 2004; 10.1152 10. /ajplung.00005.2004-eicosatetraenoic acid (5-oxo-ETE) is a proinflammatory mediator, but its effects on airway smooth muscle (ASM) have never been assessed. Tension measurements performed on guinea pig ASM showed that 5-oxo-ETE induced sustained concentration-dependent positive inotropic responses (EC 50 ϭ 0.89 M) of somewhat lower amplitude than those induced by carbamylcholine and the thromboxane A 2 (TXA2) agonist U-46619. Transient inotropic responses to 5-oxo-ETE were recorded in Ca 2ϩ -free medium, suggesting mobilization of intracellular Ca 2ϩ . Meanwhile, the sustained contraction, which required Ca 2ϩ entry, was partially blocked by 1 M nifedipine (an L-type Ca 2ϩ channel blocker) but relatively insensitive to 100 M Gd 3ϩ . The 5-oxo-ETE responses were also inhibited by indomethacin and SC-560 [a cyclooxygenase (COX-1) inhibitor] pretreatments but not by NS-398 (a selective COX-2 inhibitor). The contractile effects of 5-oxo-ETE on ASM were inhibited by the selective TXA 2 receptor (TP receptor) antagonist SQ-29548 (Ϫ75%) and by 2-(p-amylcinnamoyl) amino-4-chlorobenzoic acid pretreatment, a phospholipase A 2 inhibitor (Ϫ66%), suggesting that the major part of its effect is mediated by the release of TXA 2. ASM responses to 5-oxo-ETE were also blocked by the Rho-kinase inhibitor Y-27632, which also partially inhibited the response to the TP receptor agonist U-46619, suggesting that the contractile response is due in part to Ca 2ϩ sensitization of ASM cell myofilaments.5-oxo-eicosatetraenoic acid; isometric tension; membrane potential; calcium entry; transient receptor potential; Rho-kinase INFLAMMATORY MEDIATORS, including both lipids and peptides, induce an elaborate variety of physiological and pharmacological responses that are mediated by specific receptors coupled to various effectors (11,21,23,30). A number of inflammatory lipids are derived from arachidonic acid (AA), a cell membrane component that is found esterified in the sn-2 position on the glycerol backbone of phospholipids. AA is hydrolyzed principally by cytosolic phospholipase A 2 (cPLA 2 ) and then metabolized by various enzymes, including cyclooxygenases 1 and 2 (COX-1 and COX-2), which initiate the formation of prostaglandins (PGs) and thromboxanes (TXs), and 5-lipoxygenase, which initiates the formation of leukotrienes (LTs) and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) (8). AA is also metabolized by a number of other lipoxygenases to monohydroxy products (HETEs) and lipoxins (8) as well as by cytochrome P-450, which produces epoxyeicosatrienoic acids (EETs) and 20-HETE (35). 5-Lipoxygenase initially converts AA to 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is either further converted to LTA 4 by 5-lipoxygenase or reduced to 5-HETE by peroxidase. The latter compound can then be oxidized by 5-hydroxyeicosa...

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Nitric oxide contributes to 20-HETE-induced relaxation of pulmonary arteries

Cited by 38 publications

References 32 publications

Inhibition of 20-HETE abolishes the myogenic response during NOS antagonism in the ovine fetal pulmonary circulation

Inhibition of 20-HETE abolishes the myogenic response during NOS antagonism in the ovine fetal pulmonary circulation

20-HETE-induced nitric oxide production in pulmonary artery endothelial cells is mediated by NADPH oxidase, H₂O₂, and PI3-kinase/Akt

5-Oxo-ETE regulates tone of guinea pig airway smooth muscle via activation of Ca²⁺pools and Rho-kinase pathway

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Nitric oxide contributes to 20-HETE-induced relaxation of pulmonary arteries

Cited by 38 publications

References 32 publications

Inhibition of 20-HETE abolishes the myogenic response during NOS antagonism in the ovine fetal pulmonary circulation

Inhibition of 20-HETE abolishes the myogenic response during NOS antagonism in the ovine fetal pulmonary circulation

20-HETE-induced nitric oxide production in pulmonary artery endothelial cells is mediated by NADPH oxidase, H2O2, and PI3-kinase/Akt

5-Oxo-ETE regulates tone of guinea pig airway smooth muscle via activation of Ca2+pools and Rho-kinase pathway

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20-HETE-induced nitric oxide production in pulmonary artery endothelial cells is mediated by NADPH oxidase, H₂O₂, and PI3-kinase/Akt

5-Oxo-ETE regulates tone of guinea pig airway smooth muscle via activation of Ca²⁺pools and Rho-kinase pathway