Circulation. 2003;108:1499-1505
Published online before print September 2, 2003, doi: 10.1161/01.CIR.0000089129.51288.BA
Published online before print September 2, 2003, doi: 10.1161/01.CIR.0000089129.51288.BA
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(Circulation. 2003;108:1499.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Connective Tissue Growth Factor Is a Mediator of Angiotensin II–Induced Fibrosis
From the Vascular and Renal Research Laboratory, Autónoma University, Fundación Jiménez Diaz, Universidad Autónoma, Madrid, Spain.
Correspondence to Marta Ruiz-Ortega, Vascular and Renal Research Laboratory, Autónoma University, Fundación Jiménez Díaz, Avda Reyes Católicos, 2, 28040 Madrid, Spain. E-mail mruizo{at}fjd.es
Received March 29, 2002; de novo received March 25, 2003; revision received May 30, 2003; accepted June 3, 2003.
Background— Angiotensin II (Ang II) participates in the development of fibrosis during vascular damage. Connective tissue growth factor (CTGF) is a novel fibrotic mediator. However, the potential link between CTGF and Ang II has not been investigated.
Methods and Results— In vivo Ang II effects were studied by systemic infusion into normal rats to evaluate CTGF and extracellular matrix protein (ECM) expression by immunohistochemistry. In aorta of Ang II–infused rats, CTGF staining was markedly increased and ECM overexpression was observed. An AT1 antagonist diminished CTGF and ECM. In growth-arrested vascular smooth muscle cells, Ang II induced CTGF mRNA expression after 1 hour, remained elevated up to 24 hours, and increased CTGF protein production, which was increased up to 72 hours. The AT1 antagonist blocked Ang II–induced CTGF gene and protein expression. Early CTGF upregulation is independent of new protein synthesis. Several intracellular signals elicited by Ang II are involved in CTGF synthesis, including protein kinase C activation, reactive oxygen species, and transforming growth factor-ß endogenous production. Incubation with a CTGF antisense oligonucleotide decreased CTGF and fibronectin upregulation caused by Ang II.
Conclusions— Our results show that Ang II, via AT1, increases CTGF in vascular cells both in vivo and in vitro. This novel finding suggests that CTGF may be a mediator of the profibrogenic effects of Ang II in vascular diseases.
Key Words: angiotensin • muscle, smooth • cardiovascular diseases
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