Published online before print April 14, 2005, doi: 10.1161/01.RES.0000166326.91395.74
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Submitted on June 7, 2004
Revised on April 5, 2005
Accepted on April 6, 2005
Angiotensin IV Activates the Nuclear Transcription Factor-
B and Related Proinflammatory Genes in Vascular Smooth Muscle Cells
Vanesa Esteban ;
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.
* To whom correspondence should be addressed. 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 AT1a 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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