on August 28, 2003
Published online before print August 28, 2003, doi: 10.1161/01.ATV.0000092913.60428.E6
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Submitted on July 21, 2003
Accepted on July 31, 2003
Induction of Connective Tissue Growth Factor by Angiotensin II. Integration of Signaling Pathways
Dominika Iwanciw ;
From the Medizinische Klinik IV, Universität Erlangen-Nürnberg, Erlangen, Germany.
* To whom correspondence should be addressed. E-mail: Goppelt-Struebe{at}rzmail.uni-erlangen.de.
Objective--Angiotensin II is recognized as 1 of the major mediators of cardiovascular pathology. Because connective tissue growth factor (CTGF) is involved in the pathophysiologic processes underlying fibrotic diseases, its regulation by angiotensin II was investigated.
Methods and Results--In the 2-kidney, 1-clip model of renovascular hypertension, increased expression of CTGF was detectable in the hypertrophic left ventricle. By activation of angiotensin II type 1 receptors, angiotensin II caused rapid expression of CTGF mRNA and protein in a human fibroblast cell line. Activation of the p42/44 mitogen-activated protein (MAP) kinase signaling pathway proved to be essential for angiotensin II-stimulated CTGF expression. Inhibition of MAP kinase activation by forskolin prevented CTGF induction. Inhibition of the isoprenylation of small GTPases by simvastatin or pretreatment of the cells with toxin B reduced basal CTGF expression below detection limits and prevented induction by angiotensin II. Specific interference with RhoA signaling by Y27632 primarily reduced basal CTGF expression. There was no significant reduction of expression of angiotensin II type 1 receptors by simvastatin. These data indicate cooperation between the Rho signaling and the angiotensin II-activated MAP kinase pathways.
Conclusions--Direct induction of CTGF by angiotensin II is indicative of a role for CTGF in angiotensin II-mediated fibrosis and might be a target of antifibrotic interventions.
Key words: connective tissue growth factor • angiotensin II • Rho proteins • mitogen-activated protein kinase • statins
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