Angiotensin II induces fibronectin expression associated with cardiac fibrosis in the rat.
Fibronectin expression was studied in the heart of rats given a continuous infusion of angiotensin II (Ang II). Northern blot analysis showed that left ventricular fibronectin steady-state mRNA increased fivefold to eightfold in response to pressor doses of Ang II after 24 hours. Accumulation of immunodetectable fibronectin in the ventricles occurred after the mRNA levels increased. The changes in fibronectin expression were reversible when Ang II treatment was withdrawn. The Ang II-induced increase in fibronectin mRNA accompanied similar increases for collagen type I, collagen type IV, and atrial natriuretic factor steady-state mRNA. Interstitial and perivascular fibrosis was identified in both ventricles of angiotensin-treated rats within 3 days. In situ hybridization identified cells associated with areas of fibrosis as the principal site of fibronectin mRNA accumulation in treated animals. By comparison, normal hearts showed fibronectin expression primarily within ventricular vascular tissue and the atrial endocardium. A dose-dependent reduction of fibronectin expression followed treatment with losartan, indicating an Ang II type 1 receptor-mediated effect. Normalization of blood pressure during Ang II infusion by either hydralazine or prazosin had different effects on the level of fibronectin steady-state mRNA, indicating that blood pressure elevation was not the principal factor responsible for fibronectin induction. Concurrent administration of angiotensin-converting enzyme inhibitors with Ang II attenuated the increased fibronectin expression. Our data indicate that Ang II induces an acute fibrotic response within the heart and suggests that Ang II stimulates fibronectin expression within nonmyocytic cardiac cells by a direct action.
Crawford
D C
DC
Department of Biochemistry, Boston University School of Medicine, MA 02118.
Chobanian
A V
AV
Brecher
P
P
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000378:metabolism*; D005353:Fibronectins / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D005353:Fibronectins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor