Angiotensin IV activates the nuclear transcription factor-kappaB and related proinflammatory genes in vascular smooth muscle cells

Vanesa Esteban, Mónica Ruperez, Elsa Sánchez-López, Juan Rodríguez-Vita, Oscar Lorenzo, Heidi Demaegdt, Patrick Vanderheyden, Jesús Egido, Marta Ruiz-Ortega

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87 Citations (Scopus)


Inflammation is a key event in the development of atherosclerosis. Nuclear factor-kappaB (NF-kappaB) is important in the inflammatory response regulation. The effector peptide of the renin angiotensin system Angiotensin II (Ang II) activates NF-kappaB and upregulates some related proinflammatory genes. Our aim was to investigate whether other angiotensin-related peptides, as the N-terminal degradation peptide Ang IV, could regulate proinflammatory factors (activation of NF-kappaB and related genes) in cultured vascular smooth muscle cells (VSMCs). In these cells, Ang IV increased NF-kappaB DNA binding activity, caused nuclear translocation of p50/p65 subunits, cytosolic IkappaB degradation and induced NF-kappaB-dependent gene transcription. Ang II activates NF-kappaB via AT1 and AT2 receptors, but AT1 or AT2 antagonists did not inhibit NF-kappaB activation caused by Ang IV. In VSMC from AT1a receptor knockout mice, Ang IV also activated NF-kappaB pathway. In those cells, the AT4 antagonist divalinal diminished dose-dependently Ang IV-induced NF-kappaB activation and prevented IkappaB degradation, but had no effect on the Ang II response, indicating that Ang IV activates the NF-kappaB pathway via AT4 receptors. Ang IV also increased the expression of proinflammatory factors under NF-kappaB control, such as MCP-1, IL-6, TNF-alpha, ICAM-1, and PAI-1, which were blocked by the AT4 antagonist. Our results reveal that Ang IV, via AT4 receptors, activates NF-kappaB pathway and increases proinflammatory genes. These data indicate that Ang IV possesses proinflammatory properties, suggesting that this Ang degradation peptide could participate in the pathogenesis of cardiovascular diseases.

Original languageEnglish
Pages (from-to)965-973
Number of pages9
JournalCirculation Research
Issue number9
Publication statusPublished - 2005


  • Angiotensin II
  • Animals
  • Cells, Cultured
  • Inflammation Mediators
  • Mice
  • Mice, Knockout
  • Muscle, Smooth, Vascular
  • NF-kappa B
  • Rats
  • Rats, Inbred WKY
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin
  • Transcriptional Activation
  • Research Support, Non-U.S. Gov't


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