Circulation. 2005;111:2509-2517
Published online before print May 9, 2005,
doi: 10.1161/01.CIR.0000165133.84978.E2
(Circulation. 2005;111:2509-2517.)
© 2005 American Heart Association, Inc.
Angiotensin II Activates the Smad Pathway in Vascular Smooth Muscle Cells by a Transforming Growth Factor-ß–Independent Mechanism
Juan Rodríguez-Vita, BSc;
Elsa Sánchez-López, BSc;
Vanesa Esteban, BSc;
Mónica Rupérez, BSc;
Jesús Egido, MD;
Marta Ruiz-Ortega, PhD
From the Vascular and Renal Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
Correspondence to Marta Ruiz-Ortega, PhD, Vascular and Renal Research Laboratory, Fundación Jiménez Díaz, Avda Reyes Católicos 2, 28040 Madrid, Spain. E-mail mruizo{at}fjd.es
Received June 12, 2004; revision received December 15, 2004; accepted January 11, 2005.
Background— Angiotensin II (Ang II) participates in vascular fibrosis. Transforming growth factor-ß (TGF-ß) is considered the most important fibrotic factor, and Smad proteins are essential components of the TGF-ß signaling system. Our aim was to investigate whether Ang II activates the Smad pathway in vascular cells and its potential role in fibrosis, evaluating connective tissue growth factor (CTGF) and extracellular matrix (ECM) proteins.
Methods and Results— Systemic infusion of Ang II into Wistar rats increased aortic Smad2, phosphorylated-Smad2, and Smad4 expression, associated with CTGF upregulation. In growth-arrested vascular smooth muscle cells, Ang II treatment for 20 minutes caused Smad2 phosphorylation, nuclear translocation of phosphorylated-Smad2 and Smad4, and increased Smad DNA-binding activity. Ang II also caused Smad overexpression and Smad-dependent gene transcription. The AT1 antagonist losartan diminished Ang II-induced Smad activation. The blockade of endogenous TGF-ß did not modify the activation of Smad caused by Ang II. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 diminished Ang II-induced Smad2 phosphorylation. These data show that Ang II activates the Smad pathway via AT1 receptors and MAPK activation independently of TGF-ß. Transient transfection with Smad7, which interferes with receptor-mediated activation of Smad2, diminished Ang II-induced CTGF promoter activation, gene and protein expression, and fibronectin and type-1 procollagen overexpression, showing that Smad activation is involved in Ang II-induced fibrosis.
Conclusions— Our results show that Ang II activates the Smad signaling system in vascular cells in vivo and in vitro. Smad proteins are involved in Ang II-induced CTGF and ECM overexpression independently of TGF-ß. This novel finding suggests that Smad activation could be involved in the profibrogenic effects of Ang II in vascular diseases.
Key Words: angiotensin • cells • signal transduction • fibrosis
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