Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia-inducible factor-1 (HIF-1) takes part in the transcriptional activation of hypoxia-responsive genes. HIF-1alpha, a subunit of HIF-1, is rapidly degraded under normoxic conditions by the ubiquitin-proteosome system. Hypoxia up-regulates HIF-1alpha by inhibiting its degradation, thereby allowing it to accumulate to high levels with 3-6 h of hypoxia treatment and decreasing thereafter. In vascular tissues, prostacyclin (prostaglandin I(2) (PGI(2))) is a potent vasodilator and inhibitor of platelet aggregation and is known as a vasoprotective molecule. However, the role of PGI(2) in HIF-1 activation has not been studied. In the present study, we investigated the effect of PGI(2) on HIF-1 regulation in human umbilical vein endothelial cells under prolonged hypoxia (12 h). Augmentation of PGI(2) via adenovirus-mediated gene transfer of both cyclooxygenase-1 and PGI(2) synthase activated HIF-1 by stabilizing HIF-1alpha in cells under prolonged hypoxia or the hypoxia-normoxia transition but not under normoxia. Exogenous H(2)O(2) abolished PGI(2)- and catalase-induced HIF-1alpha up-regulation, which suggests that degradation of HIF-1alpha under prolonged hypoxia is through a reactive oxygen species-dependent pathway. Moreover, PGI(2) attenuated NADPH oxidase activity by suppressing Rac1 and p47(phox) expression under hypoxia. These data demonstrate a novel function of PGI(2) in down-regulating reactive oxygen species production by attenuating NADPH oxidase activity, which stabilizes HIF-1alpha in human umbilical vein endothelial cells exposed to prolonged hypoxia.
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PMID:Stabilization of hypoxia-inducible factor-1{alpha} by prostacyclin under prolonged hypoxia via reducing reactive oxygen species level in endothelial cells. 1611 91

The heart is unable to synthesize L-carnitine and is strictly dependent on the L-carnitine provided by the blood stream; however, additional studies are needed to better understand the mechanism of L-carnitine supplementation to the heart. The aim of this study was to evaluate the effects of L-carnitine on angiotensin II (Ang II)-induced cardiac fibroblast proliferation and to explore its intracellular mechanism(s). Cultured rat cardiac fibroblasts were pretreated with L-carnitine (1-30 mM) then stimulated with Ang II (100 nM). Ang II increased fibroblast proliferation and endothelin-1 expression, which were partially inhibited by L-carnitine. L-carnitine also attenuated Ang II-induced NADPH oxidase activity, reactive oxygen species formation, extracellular signal-regulated kinase phosphorylation, activator protein-1-mediated reporter activity and sphingosine-1-phosphate generation. In addition, L-carnitine increased prostacyclin (PGI(2)) generation in cardiac fibroblasts. siRNA transfection of PGI(2) synthase significantly reduced L-carnitine-induced PGI(2) and its anti-proliferation effects on cardiac fibroblasts. Furthermore, blockading potential PGI(2) receptors, including immunoprecipitation (IP) receptors and peroxisome proliferator-activated receptors alpha (PPAR alpha) and delta, revealed that siRNA-mediated blockage of PPAR alpha considerably reduced the anti-proliferation effect of L-carnitine. In summary, these results suggest that L-carnitine attenuates Ang II-induced effects (including NADPH oxidase activation, sphingosine-1-phosphate generation and cell proliferation) in part through PGI(2) and PPAR alpha-signaling pathways.
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PMID:L-Carnitine attenuates angiotensin II-induced proliferation of cardiac fibroblasts: role of NADPH oxidase inhibition and decreased sphingosine-1-phosphate generation. 1944 19