Lung antioxidant enzymes are regulated by development and increased pulmonary blood flow

Sharma, Shruti; Grobe, Albert C.; Wiseman, Dean A.; Kumar, Sanjiv; Englaish, Manal; Najwer, Ida; Benavidez, Eileen; Oishi, Peter; Azakie, Anthony; Fineman, Jeffrey R.; Black, Stephen M.

doi:10.1152/ajplung.00449.2006

Cited by 30 publications

(31 citation statements)

References 25 publications

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“…However, cellular levels of H 2 O 2 can be increased in the face of constant superoxide generation if the levels of scavenging are attenuated. Indeed, we have previously shown that increases in shear stress in vivo can result in decreased catalase expression and activity (44). Furthermore, it has also been previously reported that laminar shear stress (10 dyn/cm 2 , 16 h) decreases catalase activity as well as the activities of other phase 2 detoxifying enzymes (glutathione reductase, glutathione peroxidase, and glutathione S-transferase) in human umbilical vein ECs (20).…”

Section: Discussionmentioning

confidence: 69%

Shear stress stimulates nitric oxide signaling in pulmonary arterial endothelial cells via a reduction in catalase activity: role of protein kinase Cδ

Kumar

Sud

Fonseca

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Previous studies have indicated that acute increases in shear stress can stimulate endothelial nitric oxide synthase (eNOS) activity through increased PI3 kinase/Akt signaling and phosphorylation of Ser1177. However, the mechanism by which shear stress activates this pathway has not been adequately resolved nor has the potential role of reactive oxygen species (ROS) been evaluated. Thus, the purpose of this study was to determine if shear-mediated increases in ROS play a role in stimulating Ser1177 phosphorylation and NO signaling in pulmonary arterial endothelial cells (PAEC) exposed to acute increases in shear stress. Our initial studies demonstrated that although shear stress did not increase superoxide levels in PAEC, there was an increase in H2O2 levels. The increases in H2O2 were associated with a decrease in catalase activity but not protein levels. In addition, we found that acute shear stress caused an increase in eNOS phosphorylation at Ser1177 phosphorylation and a decrease in phosphorylation at Thr495. We also found that the overexpression of catalase significantly attenuated the shear-mediated increases in H2O2, phospho-Ser1177 eNOS, and NO generation. Further investigation identified a decrease in PKCdelta activity in response to shear stress, and the overexpression of PKCdelta attenuated the shear-mediated decrease in Thr495 phosphorylation and the increase in NO generation, and this led to increased eNOS uncoupling. PKCdelta overexpression also attenuated Ser1177 phosphorylation through a posttranslational increase in catalase activity, mediated via a serine phosphorylation event, reducing shear-mediated increases in H2O2. Together, our data indicate that shear stress decreases PKCdelta activity, altering the phosphorylation pattern catalase, leading to decreased catalase activity and increased H2O2 signaling, and this in turn leads to increases in phosphorylation of eNOS at Ser1177 and NO generation.

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Section: Discussionmentioning

confidence: 69%

Shear stress stimulates nitric oxide signaling in pulmonary arterial endothelial cells via a reduction in catalase activity: role of protein kinase Cδ

Kumar

Sud

Fonseca

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…This suggests that the antioxidant capacity of the cells may also affect the eNOS expression. Recently, we have reported that, in the lamb, lung antioxidant enzymes catalase, SOD1, and SOD2 are regulated both by development and by increased pulmonary blood flow (39). Additional research is therefore warranted to characterize further the complex redox regulation of eNOS expression in ECs.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen peroxide decreases endothelial nitric oxide synthase promoter activity through the inhibition of AP-1 activity

Kumar

Sun

Wedgwood³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Previously, we have reported that endothelial nitric oxide synthase (eNOS) promoter activity is decreased in pulmonary arterial endothelial cells (PAECs) in response to hydrogen peroxide (H(2)O(2)). Thus the objective of this study was to identify the cis-element(s) and transcription factor(s) responsible for oxidant-mediated downregulation of the eNOS gene. Initial promoter experiments in PAECs treated with H(2)O(2) revealed a significant decrease in activity of a promoter fragment containing 840 bp of upstream sequence of the human eNOS gene fused to a luciferase reporter. However, a promoter construct containing only 640 bp of upstream sequence had a significantly attenuated response to H(2)O(2) challenge. As the 840-bp promoter construct had a putative binding site for the transcription factor activator protein-1 (AP-1) that was lacking in the 640-bp construct, we evaluated the effect of H(2)O(2) on promoter activity after mutation of the AP-1 binding sequence (TGAGTCA at -661 to TGAGTtg in the 840-bp construct). Similar to the results seen with the 640 bp, the AP-1 mutant promoter had a significantly attenuated response to H(2)O(2). EMSA revealed decreased binding of AP-1 during H(2)O(2) treatment. Supershift analysis indicated that the AP-1 complex consisted of a c-Jun and FosB heterodimer. Furthermore, in vitro EMSA analysis indicated the c-Jun binding was significantly decreased after H(2)O(2) exposure. Using chromatin immunoprecipitation analysis, we demonstrated decreased binding of AP-1 to the eNOS promoter in vivo in response to H(2)O(2). These data suggest a role of decreased AP-1 binding likely through c-Jun in the H(2)O(2)-mediated decrease in eNOS promoter activity.

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“…Archer et al described an epigenetic attenuation of Sod2 in pulmonary arterial hypertension (3). In contrast, Sod2 expression was up-regulated over time in a lamb model of increased postnatal pulmonary blood flow, secondary to in utero aortopulmonary graft placement (77). In human IPAH, Fijalkowska et al observed a decreased Sod2 expression, but this decrease was shown in endothelial cells only (27).…”

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confidence: 94%

Function of NADPH Oxidase 1 in Pulmonary Arterial Smooth Muscle Cells After Monocrotaline-Induced Pulmonary Vascular Remodeling

Veit

Pak

Egemnazarov

et al. 2013

Antioxidants & Redox Signaling

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Lung antioxidant enzymes are regulated by development and increased pulmonary blood flow

Cited by 30 publications

References 25 publications

Shear stress stimulates nitric oxide signaling in pulmonary arterial endothelial cells via a reduction in catalase activity: role of protein kinase Cδ

Shear stress stimulates nitric oxide signaling in pulmonary arterial endothelial cells via a reduction in catalase activity: role of protein kinase Cδ

Hydrogen peroxide decreases endothelial nitric oxide synthase promoter activity through the inhibition of AP-1 activity

Function of NADPH Oxidase 1 in Pulmonary Arterial Smooth Muscle Cells After Monocrotaline-Induced Pulmonary Vascular Remodeling

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