Connective tissue growth factor is a mediator of angiotensin II-induced fibrosis

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 AT(1) 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 AT(1) 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-beta 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 AT(1), 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.