Angiotensin-converting enzyme (ACE) inhibition attenuates insulin-like growth factor-I (IGF-I) induced cardiac fibroblast proliferation

Abstract

1 The effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin type 1 (AT1) receptor blockade on insulin-like growth factor-I (IGF-I) induced proliferation and immediate-earlygene expression of neonatal rat cardiac fibroblasts were investigated. Moreover the role of the IGF-I receptor (IGF-IR) in this process was evaluated. 2 IGF-I (10-9-10-7 M) stimulated neonatal rat cardiac fibroblast growth in a dose-dependent fashion (maximum: 3.5±0.1 fold, 10-7 M), as determined by 5-bromo-2′-deoxyuridine (BrdU) incorporation. ACE inhibition or AT1 receptor blockade attenuated the IGF-I (10-7 M) induced neonatal rat cardiac fibroblast growth in a concentration-dependent fashion (moexiprilat: 50±2%, enalaprilat: 31±2%, CV11974; 58±1%, all: 10-7 M). 3 IGF-I stimulated cellular growth was accompanied by an upregulation of the immediate early genes c-Fos (2.4±0.3 fold), Egr-1 (4.7±1.1 fold) and Spl (6.2±0.7 fold). IGF-I induced expression was completely inhibited by ACE inhibition or AT1 receptor blockade. 4 Stimulation with IGF-I or Ang II (10-7 M) increased IGF-IR expression 5.7±0.5 fold and 3.6±0.5 fold respectively. The IGF-I induced overexpression of the IGF-IR was reduced by ACE inhibition with moexiprilat (10-7 M) by 79±7% and by AT1 receptor blockade with CV11974 (10-7 M) by 79±5%. 5 These data demonstrate that the mitogenic action of IGF-I in neonatal rat cardiac fibroblasts is in part mediated by activation of the renin-angiotensin system (RAS) with subsequent upregulation of IGF-IR expression. This observation has important implications for the treatment of cardiac diseases with ACE inhibitors alone and their combination with IGF-I or growth hormone.