Inhibition of 5-lipoxygenase-activating protein (FLAP) reduces pulmonary vascular reactivity and pulmonary hypertension in hypoxic rats.

Voelkel, Norbert F.; Tuder, Rubin M.; Wade, Kelly C.; Höper, Marius M.; Lepley, Robert A.; Goulet, Jennifer L.; Koller, Beverly H.; Fitzpatrick, F. A.

doi:10.1172/jci118696

Cited by 122 publications

(76 citation statements)

References 32 publications

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“…In this study, 5-LO mRNA expression was undetectable in HPMVEC at resting stage by both RPA and qRT-PCR, which was induced upon PlGF treatment. Our findings of PlGF-induced 5-LO expression in HPMVEC are consistent with previous studies of increased 5-LO expression in PAEC of patients with primary pulmonary hypertension (54) and in rats exposed to chronic hypoxia (46). Our results showed that PlGF up-regulates FLAP mRNA expression by activation of PI3K, NADPH oxidase, and HIF-1␣ in HPMVEC as reported previously for PlGF-induced FLAP expression in THP-1 monocytes (13).…”

Section: Discussionsupporting

confidence: 93%

Placenta Growth Factor-induced Early Growth Response 1 (Egr-1) Regulates Hypoxia-inducible Factor-1α (HIF-1α) in Endothelial Cells

Patel¹,

Kalra

2010

Journal of Biological Chemistry

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Leukotrienes, the lipid inflammatory products derived from arachidonic acid, are involved in the pathogenesis of respiratory and cardiovascular diseases and reactive airway disease in sickle cell disease. Placenta growth factor (PlGF), elaborated from erythroid cells, increased the mRNA expression of 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) in human pulmonary microvascular endothelial cells. PlGF-induced both promoter activity and mRNA expression of hypoxia-inducible factor-1␣ (HIF-1␣), which was abrogated by early growth response-1 (EGR-1) small interfering RNA. PlGF showed a temporal reciprocal relationship in the mRNA levels of EGR-1 and NAB2, the latter a repressor of Egr-1. Moreover, Nab2, but not mutant Nab2, significantly reduced promoter activity and mRNA expression of HIF-1␣ and also reduced expression of the HIF-1␣ target gene FLAP. Furthermore, overexpression of Egr-1 led to increased promoter activities for both HIF-1␣ and FLAP in the absence of PlGF. Additionally, the Egr-1-mediated induction of HIF-1␣ and FLAP promoters was reduced to basal levels by EGR-1 small interfering RNA. The binding of Egr-1 to HIF-1␣ promoter was corroborated by electrophoretic mobility shift assay and chromatin immunoprecipitation assay, which showed increased Egr-1 binding to the HIF-1␣ promoter in response to PlGF stimulation. These studies provide a novel mechanism for PlGF-mediated regulation of HIF-1␣ via Egr-1, which results in increased FLAP expression. This study provides a new therapeutic target, namely Egr-1, for attenuation of elevated leukotriene levels in patients with sickle cell disease and other inflammatory diseases.

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Section: Discussionsupporting

confidence: 93%

Placenta Growth Factor-induced Early Growth Response 1 (Egr-1) Regulates Hypoxia-inducible Factor-1α (HIF-1α) in Endothelial Cells

Patel¹,

Kalra

2010

Journal of Biological Chemistry

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“…The administration of 5-LOX inhibitors, zileuton or MK-886, prevented the development of pulmonary hypertension. It has also been shown that inhibition of FLAP reduced pulmonary vascular reactivity in vitro and the development of pulmonary hypertension in hypoxic rats [41]. Moreover, the antagonists of CysLT1 receptor were found to inhibit the hyperplasia of tunica intima resulting from vascular injury in various animal models [10].…”

Section: Leukotrienes and Systemic Sclerosismentioning

confidence: 98%

The role of leukotrienes in the pathogenesis of systemic sclerosis

Chwieśko-Minarowska

Kowal

Bielecki

et al. 2012

Folia Histochem Cytobiol.

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Systemic sclerosis (SSc, scleroderma) is an autoimmune disease characterized by widespread vascular injury and progressive fibrosis of the skin and internal organs. SSc-related involvement of the lungs, heart, kidneys and/or the gastrointestinal system accounts for the increased mortality of scleroderma patients. Despite the progress which has recently been made in this field, the treatment of SSc is still unsatisfactory due to the low efficacy and/or high toxicity of available therapies. Leukotrienes are a family of lipid mediators synthesized from arachidonic acid in a process mediated by 5-lipoxygenase; they include leukotriene B4 and a group of cysteinyl leukotrienes: C4, D4, and E4. Leukotrienes play an important role in the regulation of all the processes vital to the pathogenesis of SSc, namely inflammation, vascular function and connective tissue remodeling. The available data suggests that an excessive synthesis of leukotrienes may contribute to the development and progression of SSc. Accordingly, blockade of leukotriene pathways appears to be a new, promising target for the treatment of

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“…Also human bronchial fibroblasts can produce both LT B4 and cysteinyl LTs 9) . Hypoxia-induced chronic pulmonary hypertension 10) and bleomycin-induced pulmonary fibrosis in mice are characterized by overproduction of cysteinyl LTs and are significantly ameliorated in 5-lipoxygenase knockout mice 11) . The experimental study of Shimbori et al 12) recently proved the role of LTs in silica-induced pulmonary fibrosis in mice.…”

Section: Introductionmentioning

confidence: 99%

Leukotrienes B4, C4, D4 and E4 in the Exhaled Breath Condensate (EBC), Blood and Urine in Patients with Pneumoconiosis

Pelclová¹,

Fenclová²,

Vlčková³

et al. 2012

Ind Health

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Leukotrienes (LTs) are involved in the pathogenesis of lung fibrosis and were increased in exhaled breath condensate (EBC) of the patients with pneumoconiosis. However the possible influence of extra-pulmonary disorders on the EBC markers is not known. Therefore in parallel with EBC, LTs' levels in the plasma and urine were measured in patients with pneumoconiosis (45 × asbestos exposure, 37 × silica exposure) and in 27 controls. Individual LTs B4, C4, D4 and E4 were measured by liquid chromatography − electrospray ionization − tandem mass spectrometry (LC-ESI-MS/MS). In EBC, LT D4 and LT E4 were increased in both groups of patients (p<0.001 and p<0.05), comparing with the controls. Both LT B4 and cysteinyl LTs were elevated in asbestosexposed subjects (p<0.05). Asbestosis with more severe radiological signs (s1/s2-t3/u2) and lung functions impairment has shown higher cysteinyl LTs and LT C4 in the EBC (p<0.05) than mild asbestosis (s1/s0-s1/s1). In addition, in the subjects with asbestosis, cysteinyl LTs in EBC correlated with TLC (−0.313, p<0.05) and TLCO/Hb (−0.307, p<0.05), and LT C4 with TLC (−0.358, p<0.05). In pneumoconioses, EBC appears the most useful from the 3 fluids studied.

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Inhibition of 5-lipoxygenase-activating protein (FLAP) reduces pulmonary vascular reactivity and pulmonary hypertension in hypoxic rats.

Cited by 122 publications

References 32 publications

Placenta Growth Factor-induced Early Growth Response 1 (Egr-1) Regulates Hypoxia-inducible Factor-1α (HIF-1α) in Endothelial Cells

Placenta Growth Factor-induced Early Growth Response 1 (Egr-1) Regulates Hypoxia-inducible Factor-1α (HIF-1α) in Endothelial Cells

The role of leukotrienes in the pathogenesis of systemic sclerosis

Leukotrienes B4, C4, D4 and E4 in the Exhaled Breath Condensate (EBC), Blood and Urine in Patients with Pneumoconiosis

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