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(Hypertension. 2000;35:978.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Angiotensin II and _vß₃ Integrin Expression in Rat Neonatal Cardiac Fibroblasts

Kristof Graf; Michael Neuss; Philipp Stawowy; Willa A. Hsueh; Eckart Fleck; Ronald E. Law

From the Division of Endocrinology, Diabetes and Hypertension (W.A.H., R.E.L.), University of California Los Angeles, School of Medicine, and the Department of Medicine/Cardiology (K.G., M.N., P.S., E.F.), Charité, Campus Virchow Klinikum, Humboldt Universität Berlin and Deutsches Herzzentrum Berlin, Berlin, Germany.

Correspondence to Dr Kristof Graf, Med Klinik m S Kardiologie, Charité, Campus Virchow Klinikum, Humboldt Universität Berlin und Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.

Abstract—We recently demonstrated that _vß₃ integrins are involved in the mechanisms of angiotensin II (Ang II)–induced DNA synthesis and collagen gel contractions in rat cardiac fibroblasts (CFBs), cellular mechanisms that are relevant for cardiac remodeling. The aim of the present study was to elucidate the effect of Ang II and other growth factors on the regulation of the _vß₃ integrins in fibroblasts from neonatal rat hearts. The _vß₃ integrin receptor expression was significantly increased (P<0.05) at the mRNA level after treatment with Ang II, transforming growth factor-ß₁ (TGF-ß₁), and platelet-derived growth factor (PDGF) for 8 and 16 hours. The surface expression of the _v and ß₃ integrin subunits was elevated after 32 and 48 hours (P<0.05) as determined with flow cytometry. To investigate fibroblast motility, we performed chemotaxis experiments with transwell chambers. Ang II was chemotactic for CFBs, as tested with checkerboard experiments. The chemotactic effect was concentration dependent and was completely blocked by Ang II type 1 receptor blockers but not by Ang II type 2 receptor blocker PD 123319. Ang II– and PDGF-BB–mediated chemotaxis could be significantly inhibited by RGD peptides and the blocking antibodies against _vß₃ integrin (both P<0.01). Adhesion of CFBs to vitronectin was partially inhibited by an antibody to _vß₃ integrin but was mainly mediated by an _vß₅ integrin. Relevant in vivo expression of _vß₃ integrin by CFBs was confirmed with in situ hybridization with probes for _v and ß₃ mRNA in rat hearts. The present study demonstrates that the expression of _vß₃ integrin is augmented by Ang II, PDGF, and TGF-ß₁ in neonatal CFBs. Furthermore, this integrin is involved in the chemotaxis, motility, and adhesion of CFBs. The present findings support the current concept that integrins participate in the control of fibroblast behavior during cardiac remodeling mechanisms.

Key Words: integrins • angiotensin II • fibroblasts • remodeling

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