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(Circulation Research. 2005;96:965.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Angiotensin IV Activates the Nuclear Transcription Factor-B 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

From the Vascular and Renal Research Laboratory (V.E., M.R., E.S.-L., J.R.-V., O.L., J.E., M.R.-O.), Fundación Jiménez Diaz, Universidad Autónoma Madrid, Spain; and the Department of Molecular and Biochemical Pharmacology (H.D., P.V.), Institute for Molecular Biology and Biotechnology, Vrije Univerisiteit Brussel, Belgium.

Correspondence to Marta Ruiz-Ortega, PhD, Vascular and Renal Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma de Madrid Avda, Reyes Católicos, 2, 28040 Madrid, Spain. E-mail mruizo{at}fjd.es

Inflammation is a key event in the development of atherosclerosis. Nuclear factor-B (NF-B) is important in the inflammatory response regulation. The effector peptide of the renin angiotensin system Angiotensin II (Ang II) activates NF-B 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-B and related genes) in cultured vascular smooth muscle cells (VSMCs). In these cells, Ang IV increased NF-B DNA binding activity, caused nuclear translocation of p50/p65 subunits, cytosolic IB degradation and induced NF-B–dependent gene transcription. Ang II activates NF-B via AT₁ and AT₂ receptors, but AT₁ or AT₂ antagonists did not inhibit NF-B activation caused by Ang IV. In VSMC from AT_1a receptor knockout mice, Ang IV also activated NF-B pathway. In those cells, the AT₄ antagonist divalinal diminished dose-dependently Ang IV–induced NF-B activation and prevented IB degradation, but had no effect on the Ang II response, indicating that Ang IV activates the NF-B pathway via AT₄ receptors. Ang IV also increased the expression of proinflammatory factors under NF-B control, such as MCP-1, IL-6, TNF-, ICAM-1, and PAI-1, which were blocked by the AT₄ antagonist. Our results reveal that Ang IV, via AT₄ receptors, activates NF-B 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.

Key Words: angiotensin IV • signal transduction • nuclear factor–B • vascular smooth muscle cell • insulin regulated aminopeptidase

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