Calcineurin expression and activity is regulated by the intracellular redox status and under hypertension in human neutrophils.
Calcineurin (protein phosphatase 2B) (CN) comprises a family of serine/threonine phosphatases that play a pivotal role in signal transduction cascades in a variety of cells, including neutrophils. Angiotensin II (Ang II) increases both activity and de novo synthesis of CN in human neutrophils. This study focuses on the role that intracellular redox status plays in the induction of CN activity by Ang II. Both de novo synthesis of CN and activity increase promoted by Ang II were downregulated when cells were treated with L-buthionine-(S,R)-sulfoximine, an inhibitor of synthesis of the antioxidant glutathione. We have also investigated the effect of pyrrolidine dithiocarbamate and phenazine methosulfate, which are antioxidant and oxidant compounds, respectively, and concluded that the intracellular redox status of neutrophils is highly critical for Ang II-induced increase of CN expression and activity. Results obtained in neutrophils from hypertensive patients were very similar to those obtained in these cells on treatment with Ang II. We have also addressed the possible functional implication of CN activation in the development of hypertension. Present findings indicate that downregulation of hemoxygenase-1 expression in neutrophils from hypertensive subjects is likely mediated by CN, which acts by hindering translocation to the nucleus of the transcription factor NRF2. These data support and extend our previous results and those from other authors on modulation of CN expression and activity levels by the intracellular redox status.
Departamento de Bioquímica Médica y Biología Molecular, Facultad de Medicina and Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla, Avenida Sánchez Pizjuán 4, E-41009 Sevilla, Spain.
Gonzalo
G
Alba
Consuelo
C
Santa-María
María Edith
ME
Reyes-Quiroz
Rajaa
R
El Bekay
Isabel
I
Geniz
José
J
Martín-Nieto
Elizabeth
E
Pintado
Francisco
F
Sobrino
D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D008773:Methylphenazonium Methosulfate / Q000494:pharmacology; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011759:Pyrrolidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013859:Thiocarbamates / Q000494:pharmacology
D000975:Antioxidants; D004791:Enzyme Inhibitors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D008773:Methylphenazonium Methosulfate; D019328:Buthionine Sulfoximine; D051547:Heme Oxygenase-1; D005980:Glutathione Reductase; D019703:Calcineurin; C525673:PPP3CA protein, human; C525674:PPP3CB protein, human; D005978:Glutathione