Angiotensin IV Activates the Nuclear Transcription Factor-κB and Related Proinflammatory Genes in Vascular Smooth Muscle Cells

• Published in: Circulation research 2005-05, Vol.96 (9), p.965-973
• Main Authors: Esteban, Vanesa, Ruperez, Mónica, Sánchez-López, Elsa, Rodríguez-Vita, Juan, Lorenzo, Oscar, Demaegdt, Heidi, Vanderheyden, Patrick, Egido, Jesús, Ruiz-Ortega, Marta
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000166326.91395.74

Inflammation is a key event in the development of atherosclerosis. Nuclear factor-κB (NF-κB) is important in the inflammatory response regulation. The effector peptide of the renin angiotensin system Angiotensin II (Ang II) activates NF-κB 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-κB and related genes) in cultured vascular smooth muscle cells (VSMCs). In these cells, Ang IV increased NF-κB DNA binding activity, caused nuclear translocation of p50/p65 subunits, cytosolic IκB degradation and induced NF-κB–dependent gene transcription. Ang II activates NF-κB via AT1 and AT2 receptors, but AT1 or AT2 antagonists did not inhibit NF-κB activation caused by Ang IV. In VSMC from AT1a receptor knockout mice, Ang IV also activated NF-κB pathway. In those cells, the AT4 antagonist divalinal diminished dose-dependently Ang IV–induced NF-κB activation and prevented IκB degradation, but had no effect on the Ang II response, indicating that Ang IV activates the NF-κB pathway via AT4 receptors. Ang IV also increased the expression of proinflammatory factors under NF-κB control, such as MCP-1, IL-6, TNF-α, ICAM-1, and PAI-1, which were blocked by the AT4 antagonist. Our results reveal that Ang IV, via AT4 receptors, activates NF-κB 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.