scholarly journals Hypoxia-inducible Factor-1 Activation in Nonhypoxic Conditions: The Essential Role of Mitochondrial-derived Reactive Oxygen Species

2010 ◽  
Vol 21 (18) ◽  
pp. 3247-3257 ◽  
Author(s):  
David A. Patten ◽  
Véronique N. Lafleur ◽  
Geneviève A. Robitaille ◽  
Denise A. Chan ◽  
Amato J. Giaccia ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Protein Stabilization ◽  
Complex Iii ◽  
Oxygen Species ◽  
Ang Ii ◽  
Hypoxia Inducible Factor 1

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor for responses to low oxygen. Different nonhypoxic stimuli, including hormones and growth factors, are also important HIF-1 activators in the vasculature. Angiotensin II (Ang II), the main effecter hormone in the renin-angiotensin system, is a potent HIF-1 activator in vascular smooth muscle cells (VSMCs). HIF-1 activation by Ang II involves intricate mechanisms of HIF-1α transcription, translation, and protein stabilization. Additionally, the generation of reactive oxygen species (ROS) is essential for HIF-1 activation during Ang II treatment. However, the role of the different VSMC ROS generators in HIF-1 activation by Ang II remains unclear. This work aims at elucidating this question. Surprisingly, repression of NADPH oxidase-generated ROS, using Vas2870, a specific inhibitor or a p22phox siRNA had no significant effect on HIF-1 accumulation by Ang II. In contrast, repression of mitochondrial-generated ROS, by complex III inhibition, by Rieske Fe-S protein siRNA, or by the mitochondrial-targeted antioxidant SkQ1, strikingly blocked HIF-1 accumulation. Furthermore, inhibition of mitochondrial-generated ROS abolished HIF-1α protein stability, HIF-1–dependent transcription and VSMC migration by Ang II. A large number of studies implicate NADPH oxidase–generated ROS in Ang II–mediated signaling pathways in VSMCs. However, our work points to mitochondrial-generated ROS as essential intermediates for HIF-1 activation in nonhypoxic conditions.

Insulin-induced activation of hypoxia-inducible factor-1 requires generation of reactive oxygen species by NADPH oxidase

2007 ◽  
Vol 292 (2) ◽  
pp. H758-H766 ◽  
Author(s):  
Sudipta Biswas ◽  
Manveen Kaur Gupta ◽  
Debasis Chattopadhyay ◽  
Chinmay K. Mukhopadhyay
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Tyrosine Phosphatase ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Sodium Vanadate ◽  
Insulin Receptor Tyrosine Kinase ◽  
Gene Assay

Hypoxia-inducible factor (HIF)-1 activation in response to hypoxia requires mitochondrial generation of reactive oxygen species (ROS). In contrast, the requirement of ROS for HIF-1 activation by growth factors like insulin remains unexplored. To explore that, insulin-sensitive hepatic cell HepG2 or cardiac muscle cell H9c2 cells were pretreated with NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) or apocynin and HIF-1 activation was tested by electrophoretic mobility shift and reporter gene assay. Antioxidants DPI or apocynin completely blocked insulin-stimulated HIF-1 activation. The restoration of HIF-1 activation by H2O2 in DPI-pretreated cells not only confirmed the role of ROS but also identified H2O2 as the responsible ROS. The role of NADPH oxidase was further confirmed by greater stimulation of HIF-1 during simultaneous treatment of suboptimal concentration of insulin along with NADPH but not by NADH. The role of oxidant generated by insulin is found to inhibit the protein tyrosine phosphatase as suggested by the following observations. First, tyrosine phosphatase-specific inhibitor sodium vanadate compensates DPI-inhibited HIF-1 activity. Second, sodium vanadate stimulates HIF-1 activation with suboptimal concentration of insulin. Third, DPI and pyrrolidene dithiocarbamate (PDTC) blocks insulin-receptor tyrosine kinase activation. The activity of phosphatidylinositol 3-kinase as evidenced by Akt phosphorylation, involved in HIF-1 activation, is also dependent on ROS generation by insulin. Finally, DPI pretreatment blocked insulin-stimulated expression of genes like VEGF, GLUT1, and ceruloplasmin. Overall, our data provide strong evidence for the essential role of NADPH oxidase-generated ROS in insulin-stimulated activation of HIF-1.

Reactive Oxygen Species-Mediated Homologous Downregulation of Angiotensin II Type 1 Receptor Mrna by Angiotensin II

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 688-688
Author(s):  
Toshihiro Ichiki ◽  
Kotaro Takeda ◽  
Akira Takeshita
Keyword(s):  
Reactive Oxygen Species ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Mrna Expression ◽  
Crucial Role ◽  
Oxygen Species ◽  
Ang Ii ◽  
Stimulation Of

58 Recent studies suggest a crucial role of reactive oxygen species (ROS) for the signaling of Angiotensin II (Ang II) through type 1 Ang II receptor (AT1-R). However, the role of ROS in the regulation of AT1-R expression has not been explored. In this study, we examined the effect of an antioxidant on the homologous downregulation of AT1-R by Ang II. Ang II (10 -6 mol/L) decreased AT1-R mRNA with a peak suppression at 6 hours of stimulation in rat aortic vascular smooth muscle cells (VSMC). Ang II dose-dependently (10 -8 -10 -6 ) suppressed AT1-R mRNA at 6 hours of stimulation. Preincubation of VSMC with N-acetylcysteine (NAC), a potent antioxidant, almost completely inhibited the Ang II-induced downregulation of AT1-R mRNA. The effect of NAC was due to stabilization of the AT1-R mRNA that was destabilized by Ang II. Ang II did not affect the promoter activity of AT1-R gene. Diphenylene iodonium (DPI), an inhibitor of NADH/NADPH oxidase failed to inhibit the Ang II-induced AT1-R mRNA downregulation. The Ang II-induced AT1-R mRNA downregulation was also blocked by PD98059, an extracellular signal-regulated protein kinase (ERK) kinase inhibitor. Ang II-induced ERK activation was inhibited by NAC as well as PD98059 whereas DPI did not inhibit it. To confirm the role of ROS in the regulation of AT1-R mRNA expression, VSMC were stimulated with H 2 O 2 . H 2 O 2 suppressed the AT1-R mRNA expression and activated ERK. These results suggest that production of ROS and activation of ERK are critical for downregulation of AT1-R mRNA. The differential effect of NAC and DPI on the downregulation of AT1-R mRNA may suggest the presence of other sources than NADH/NADPH oxidase pathway for ROS in Ang II signaling. Generation of ROS through stimulation of AT1-R not only mediates signaling of Ang II but may play a crucial role in the adaptation process of AT1-R to the sustained stimulation of Ang II.

scholarly journals NADPH Oxidase as a Therapeutic Target for Oxalate Induced Injury in Kidneys

2013 ◽  
Vol 2013 ◽  
pp. 1-18 ◽  
Author(s):  
Sunil Joshi ◽  
Ammon B. Peck ◽  
Saeed R. Khan
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Tissue Injury ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Reactive Oxygen ◽  
Renal Tissue ◽  
Oxygen Species ◽  
Gene Expressions

A major role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes is to catalyze the production of superoxides and other reactive oxygen species (ROS). These ROS, in turn, play a key role as messengers in cell signal transduction and cell cycling, but when they are produced in excess they can lead to oxidative stress (OS). Oxidative stress in the kidneys is now considered a major cause of renal injury and inflammation, giving rise to a variety of pathological disorders. In this review, we discuss the putative role of oxalate in producing oxidative stress via the production of reactive oxygen species by isoforms of NADPH oxidases expressed in different cellular locations of the kidneys. Most renal cells produce ROS, and recent data indicate a direct correlation between upregulated gene expressions of NADPH oxidase, ROS, and inflammation. Renal tissue expression of multiple NADPH oxidase isoforms most likely will impact the future use of different antioxidants and NADPH oxidase inhibitors to minimize OS and renal tissue injury in hyperoxaluria-induced kidney stone disease.

Increased Generation of Vascular Reactive Oxygen Species by Ang II Is Mediated Via Src-Dependent Pathways in Essential Hypertension.

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 685-685
Author(s):  
Rhian M Touyz ◽  
Ernesto L Schiffrin
Keyword(s):  
Reactive Oxygen Species ◽  
Essential Hypertension ◽  
Nadph Oxidase ◽  
Reactive Oxygen ◽  
Leucine Incorporation ◽  
Oxygen Species ◽  
Ang Ii ◽  
Growth Responses ◽  
Hypertensive Patients ◽  
In Cells

42 We tested the hypothesis that augmented Ang II-induced vascular smooth muscle cell (VSMC) growth in human hypertension is mediated via Src-dependent pathways that generate reactive oxygen species (ROS). VSMCs from arteries of normotensive and hypertensive subjects were studied. Production of ROS was measured by fluorescence digital imaging using dichlorofluorescin diacetate (6 μM). The roles of Src and NADH/NADPH oxidase were assessed with the specific inhibitors, PP2 (10 μM) and diphenylene iodinium (DPI) (10 μM) respectively. c-Src phosphorylation was determined by western blot and kinase activity was assessed by measuring enolase phosphorylation. Ang II increased DCFDA fluorescence. This effect was inhibited by catalase, indicating that the signal was derived predominantly from H 2 O 2 . Ang II increased H 2 O 2 production within 40 minutes. Responses were greater (p<0.05) in cells from hypertensive patients (E max =82±nM) than normotensive subjects (E max = 67±nM). DPI and PP2, but not PP3 (inactive analogue) attenuated (p<0.05) Ang II-induced H 2 O 2 production. PP2 effects were greater in cells from hypertensive patients (delta H 2 O 2 , 28±5nM) vs controls (delta H 2 O 2 , 16±2nM). Ang II increased c-Src phosphorylation and activity, with responses 3-4 fold higher in hypertensives. DPI and PP2 (p<0.01) attenuated Ang II-induced DNA and protein synthesis, as measured by 3 H-thymidine and 3 H-leucine incorporation respectively. Growth responses in hypertensive patients were normalized by PP2. In VSMCs from hypertensive patients, Ang II-induced generation of ROS and growth are augmented. These effects are mediated, in part, by Src-dependent, NADH/NADPH oxidase-dependent cascades. Thus increased Src activity may be an upstream modulator of redox-sensitive pathways that regulate vascular growth and remodeling in essential hypertension.

scholarly journals Reactive Oxygen Species and Nrf2: Functional and Transcriptional Regulators of Hematopoiesis

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Linping Hu ◽  
Yawen Zhang ◽  
Weimin Miao ◽  
Tao Cheng
Keyword(s):  
Reactive Oxygen Species ◽  
Oxygen Sensor ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Ambient Air ◽  
Oxygen Species ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Hypoxia Inducible Factor 1 ◽  
Cellular Oxygen

Hematopoietic stem cells (HSCs) are characterized by self-renewal and multilineage differentiation potentials. Although they play a central role in hematopoietic homeostasis and bone marrow (BM) transplantation, they are affected by multiple environmental factors in the BM. Here, we review the effects of reactive oxygen species (ROS) and Nrf2 on HSC function and BM transplantation. HSCs reside in the hypoxic microenvironment of BM, and ROS play an important role in HSPC regulation. Recently, an extraphysiologic oxygen shock/stress phenomenon was identified in human cord blood HSCs collected under ambient air conditions. Moreover, Nrf2 has been recently recognized as a master transcriptional factor that regulates multiple antioxidant enzymes. Since several years, the role of Nrf2 in hematopoiesis has been extensively studied, which has functional similarities of cellular oxygen sensor hypoxia-inducible factor-1 as transcriptional factors. Increasing evidence has revealed that abnormally elevated ROS production due to factors such as genetic defects, aging, and ionizing radiation unexceptionally resulted in lethal impairment of HSC function and hematopoiesis. Both experimental and clinical studies have identified elevated ROS levels as a major culprit of ineffective BM transplantation. Lastly, we discuss the possibility of using small molecule antioxidants, such as N-acetyl cysteine, resveratrol, and curcumin, to augment HSC function and improve the therapeutic efficacy of BM transplantation. Further research on the function of ROS levels and improving the efficacy of BM transplantation may have a great potential for broad clinical applications of HSCs.

scholarly journals Role of reactive oxygen species produced by NADPH oxidase in gibberellin biosynthesis during barley seed germination

2016 ◽  
Vol 11 (5) ◽  
pp. e1180492 ◽  
Author(s):  
Kyohei Kai ◽  
Shinsuke Kasa ◽  
Masatsugu Sakamoto ◽  
Nozomi Aoki ◽  
Gaku Watabe ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Seed Germination ◽  
Nadph Oxidase ◽  
Reactive Oxygen ◽  
Barley Seed ◽  
Gibberellin Biosynthesis ◽  
Oxygen Species
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