Enhanced expression of fibrillin-1, a constituent of the myocardial extracellular matrix in fibrosis

1 Institut de Recherches Cliniques de Montréal, Université de Montréal, Montréal; 2 Department of Medical Molecular Biology, University of Lübeck; and Department of Anatomy and Cell Biology, McGill University, Montréal, Québec, Canada Submitted 14 February 2005 ; accepted in final form 15 April 2005 Fibrillin-1 localization in the myocardium and the modulation of its expression in cardiac fibrosis were examined. In normal rat hearts, fibrillin-1 was abundant throughout the myocardium as thin fibers that crossed over the perimysium and around arteries. After cardiac fibrosis was induced in rats by either 14-day ANG II infusion or 21-day DOCA-salt treatment [a high endothelin-1 (ET-1) model], fibrillin-1 immunostaining was stronger in the interstitium (2.8-fold and 4.4-fold increases, respectively, in each model), extended between myocytes, and accumulated in microscopic scars and in the perivascular area of both ventricles. mRNA analysis confirmed its enhanced ventricular expression in both groups of rats (2.5-fold and 6.6-fold increments, respectively, in each model). In 1B normotensive and 2C hypertensive transgenic mice, two lines expressing an ANG II fusion protein in cardiac myocytes, strong fibrillin-1 immunoreactivity was observed in the interstitium and around arteries (3.7-fold and 7-fold increases, respectively). ANG II and transforming growth factor- 1 enhanced fibrillin-1 synthesis by cardiac fibroblasts. Some fibrillin-1 fragments interacted with RGD-dependent integrins, including 8 1 -integrin, of cardiac fibroblasts but not necessarily through the RGD motif. Our findings illustrate that fibrillin-1 is an important constituent of the myocardium. In vitro and in vivo evidence suggests that ANG II can directly induce fibrillin-1 expression in cardiac fibroblasts. This protein can thus contribute to reactive and reparative processes. collagen; fibronectin; cardiac fibroblasts; angiotensin II; deoxycorticosterone Address for reprint requests and other correspondence: G. Thibault, Institut de Recherches Cliniques de Montréal (IRCM), 110 Ave. Des Pins Ouest, Montréal, Québec, Canada H2W 1R7 (e-mail: thibaug{at}ircm.qc.ca )