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

The effects of angiotensin‐converting enzyme (ACE) inhibition and angiotensin type 1 (AT 1 ) receptor blockade on insulin‐like growth factor‐I (IGF‐I) induced proliferation and immediate‐early‐gene expression of neonatal rat cardiac fibroblasts were investigated. Moreover the role of the IGF‐I receptor (IGF‐IR) in this process was evaluated. 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 AT 1 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 ). 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 Sp1 (6.2±0.7 fold). IGF‐I induced expression was completely inhibited by ACE inhibition or AT 1 receptor blockade. 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 AT 1 receptor blockade with CV11974 (10 −7   M ) by 79±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.British Journal of Pharmacology (2000) 131 , 1592–1596; doi: 10.1038/sj.bjp.0703740