Abstract
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.