Ang II Promotes ET-1 Production by Regulating NOX2 Activity Through Transcription Factor Oct-1

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Julian Kamhieh-Milz - , Charité – Universitätsmedizin Berlin (Erstautor:in)
  • Lei Chen - , Charité – Universitätsmedizin Berlin, National Sun Yat-sen University (Zweitautor:in)
  • Claudia Goettsch - , Rheinisch-Westfälische Technische Hochschule Aachen, Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Anna Maria Pefferkorn - , Charité – Universitätsmedizin Berlin (Autor:in)
  • Anja Hofmann - , Klinik und Poliklinik für Viszeral-, Thorax- und Gefäßchirurgie (Autor:in)
  • Coy Brunßen - , Medizinische Klinik und Poliklinik 3 (Autor:in)
  • Gregor M. Müller - , Technische Universität Dresden (Autor:in)
  • Thomas Walther - , University College Cork, Ernst-Moritz-Arndt-Universität Greifswald (Autor:in)
  • Muhammad Imtiaz Ashraf - , Charité – Universitätsmedizin Berlin (Autor:in)
  • Guido Moll - , Charité – Universitätsmedizin Berlin (Autor:in)
  • Henning Morawietz - , Medizinische Klinik und Poliklinik 3 (Autor:in)
  • Janusz Witkowski - , University of Medical Sciences Poznan (Autor:in)
  • Rusan Ali Catar - , Charité – Universitätsmedizin Berlin (Autor:in)

Abstract

Introduction Increasing evidence suggests that superoxide ions produced by NOX (nicotinamide adenine dinucleotide phosphate oxidases) mediate vascular effects of Ang II (angiotensin II) evoked by atherogenic diets. Here, we analyzed the mechanism by which NOX2 contributes to Ang II-induced ET-1 (endothelin 1) production in human microvascular endothelial cells. Methods: The effects of high-fat diet were compared between WT (wild type) and Nox2 (mouse NOX2 gene)-deficient mice. ET-1 production and NOX2 expression by human microvascular endothelial cells in vitro were analyzed by ELISA, reverse transcription quantitative polymerase chain reaction, electrophoretic mobility shift assay, promoter deletions, RNA interference, and pharmacological inhibition. Production of superoxide anions was visualized by fluorescent cell labeling.

Results: Feeding mice high-fat diet for 10 weeks increased cardiac expression and plasma levels of Ang II and ET-1 in WT but not in Nox2-deficient animals. Exposure of human microvascular endothelial cells to Ang II resulted in increased ET-1 production, which could be blocked by silencing NOX2 (human NOX2 gene). Ang II promoted NOX2 expression through induction of the Oct-1 (human/mouse octamer binding transcription factor 1 protein) and activation of the NOX2 promoter region containing Oct-1-binding sites. Stimulation of NOX2 expression by Ang II was associated with increased production of superoxide anions. Inhibition of Oct-1 by small interfering RNA reduced Ang II-induced NOX2 expression and superoxide anion production, and neutralization of superoxide by SOD (superoxide dismutase) abolished Ang II-stimulated ET1 (human ET-1 gene) promoter activity, ET1 mRNA expression, and ET-1 release.

Conclusions: Ang II may promote ET-1 production in the endothelium in response to atherogenic diets through a mechanism that involves the transcription factor Oct-1 and the increased formation of superoxide anions by NOX2.
Titel in Übersetzung
Ang II fördert die ET-1-Produktion durch Regulierung der NOX2-Aktivität mittels des Transkriptionsfaktors Oct-1

Details

OriginalspracheEnglisch
Seiten (von - bis)1429-1440
Seitenumfang12
FachzeitschriftArteriosclerosis, Thrombosis, and Vascular Biology
Jahrgang43
Ausgabenummer8
PublikationsstatusVeröffentlicht - 2023
Peer-Review-StatusJa

Externe IDs

Scopus 85166363562
ORCID /0000-0001-9360-9736/work/164198481

Schlagworte