(Hypertension. 2000;35:273.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Angiotensin II Enhances Integrin and 
-Actinin Expression in Adult Rat Cardiac Fibroblasts
From the Department of Medicine (H.K., S.G., Y.K., J.S., R.E.L., W.A.H.), Division of Endocrinology, Diabetes and Hypertension, Molecular Biology Institute (R.E.L., W.A.H.), and Department of Medicine (J.S.), Division of Cardiology, University of California at Los Angeles School of Medicine; Department of Medicine/Cardiology (R.J.C.), University of Michigan Medical Center, Ann Arbor; and Department of Medicine/Cardiology (K.G., S.G.), Virchow Klinikum, Humboldt University Berlin and German Heart Institute Berlin, Berlin, Germany.
Correspondence to Willa A. Hsueh, MD, University of California, Los Angeles, School of Medicine, Division of Endocrinology, Diabetes and Hypertension, Warren Hall, 2nd Floor, Room 24-130, 900 Veteran Ave, Mail Code 178622, Los Angeles, CA 90024.
Abstract—Angiotensin II (Ang II) plays an important role in cardiac remodeling through stimulation of proliferation and extracellular matrix (ECM) production in cardiac fibroblasts. Integrins are a family of transmembrane receptors that mediate the attachment of cells to ECM. We hypothesized that Ang II regulation of integrins further contributes to its role in cardiac remodeling. We cultured adult rat cardiac fibroblasts with and without Ang II (100 nmol/L) to determine the effects on mRNA and protein levels of integrins, as well as 
-actinin and other cytoskeletal proteins that link to integrins at the site of focal adhesions. Ang II was also added in the presence of irbesartan (10 µmol/L), a specific Ang II type 1 (AT1) receptor antagonist, or PD 123319 (10 µmol/L), a specific Ang II type 2 receptor antagonist. To investigate the function of these integrins, we determined the effects of blocking antibodies on Ang II–induced adhesion to ECM. We also treated spontaneously hypertensive rats (SHR) with an AT1 receptor blocker, losartan, or with hydralazine to investigate integrin and -actinin expression in treated and untreated SHR. Ang II enhanced v, ß1, ß3, and ß5 integrins; osteopontin; and -actinin mRNA and protein levels in cardiac fibroblasts. All of these effects were inhibited by irbesartan but not by PD 123319. Pretreatment of cardiac fibroblasts with Ang II enhanced cell attachment to ECM proteins and induced focal adhesion kinase phosphorylation. Blocking antibodies to ß3 and vß5 attenuated Ang II–induced adhesion. In SHR, ventricular v and ß5 integrin expression and -actinin were increased compared with those in Wistar-Kyoto rats. Although both losartan and hydralazine lowered mean arterial pressure and decreased peripheral vascular resistance, only losartan attenuated the increased integrin, -actinin, fibronectin laminin, and osteopontin expression and the increased left ventricular mass (as determined with echocardiography). Hydralzine had none of these effects. Although both agents attenuated ß-myosin heavy chain expression, a marker of hypertrophy, losartan had a greater effect. These results suggest that integrins and -actinin are upregulated by Ang II and in left ventricular hypertrophy and that the block of expression of these proteins through inhibition of the AT1 receptor is associated with attenuation of the hypertrophic response. Ang II induces integrin and -actinin expression in cardiac fibroblasts that is associated with adhesion and left ventricular hypertrophy and blocked through inhibition of the AT1 receptor.
Key Words: angiotensin II • integrins • kinase
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