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(Circulation. 1998;98:2553-2559.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Expression of Functional Angiotensin-Converting Enzyme and AT₁ Receptors in Cultured Human Cardiac Fibroblasts

Sassan Hafizi, BSc; John Wharton, PhD; Kevin Morgan, PhD; Sean P. Allen, PhD; Adrian H. Chester, PhD; John D. Catravas, PhD; Julia M. Polak, FRCPath; Magdi H. Yacoub, FRCS

From the Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College School of Medicine at the Heart Science Centre, Harefield Hospital, Middlesex, UK (S.H., S.P.A., A.H.C., M.H.Y.); the Department of Histochemistry, Division of Investigative Science, Imperial College School of Medicine at Hammersmith Hospital, London, UK (J.W., K.M., J.M.P.); and the Vascular Biology Center, Medical College of Georgia, Augusta (J.D.C.).

Correspondence to Professor Sir Magdi Yacoub, FRCS, Harefield Hospital, Hill End Road, Harefield, Middlesex, UB9 6JH, UK.

Background—Angiotensin II (Ang II) has been implicated in the development of cardiac fibrosis. The aims of the present study were to examine expression and activity of ACE and of angiotensin receptors in human cardiac fibroblasts cultured from dilated cardiomyopathic and ischemic hearts. The effects of Ang II on fibroblasts were also investigated.

Methods and Results—Human cardiac fibroblasts were cultured from ventricular and atrial myocardium and characterized immunohistochemically. Expression of ACE and the angiotensin AT₁ receptor was demonstrated in cardiac fibroblasts by reverse transcriptase–polymerase chain reaction and radioligand binding. Functional ACE activity, measured by radiolabeled substrate conversion assay, was detected in both ventricular (V_max · K_m^-1 · mg^-1, 0.031±0.010; n=13) and atrial (0.034±0.012; n=6) fibroblasts. Fibroblast ACE activity was increased after 48 hours of treatment with basic fibroblast growth factor, dexamethasone, and phorbol ester. Ang II did not affect DNA synthesis but stimulated [³H]proline incorporation in cardiac fibroblasts (20.0±4.0% increase above control by 10 µmol/L; P<0.05, n=7), which was abolished by losartan 10 µmol/L but not PD123319 1 µmol/L. Ang II also stimulated a rise in intracellular calcium (basal, 56±1 nmol/L; Ang II, 355±24 nmol/L) via the AT₁ receptor, as shown by complete inhibition with losartan.

Conclusions—We have demonstrated expression and activity of ACE and AT₁ receptor in cultured human cardiac fibroblasts. In addition, cardiac fibroblasts respond to Ang II with AT₁ receptor–mediated collagen synthesis. The presence of local ACE and AT₁ receptors in human fibroblasts suggests their involvement in the development of cardiac fibrosis.

Key Words: angiotensin • receptors • enzymes • collagen • cells

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