title: Angiotensin-converting enzyme (ACE) inhibition attenuates insulin-like growth factor-I (IGF-I) induced cardiac fibroblast proliferation.
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.
authors.affiliation: Medizinische Universitäts-Poliklinik, University of Bonn, Wilhelmstrasse 35-37, 53111 Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: van Eickels
authors.forename: H
authors.initials: H
authors.lastname: Vetter
authors.forename: C
authors.initials: C
authors.lastname: Grohé
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017874:Immediate-Early Proteins; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology; D009842:Oligopeptides / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D044005:Tetrahydroisoquinolines; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D007546:Isoquinolines; D009842:Oligopeptides; D016760:Proto-Oncogene Proteins c-fos; D016329:Sp1 Transcription Factor; D044005:Tetrahydroisoquinolines; D013777:Tetrazoles; D014157:Transcription Factors; C411572:H 1356; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D001973:Bromodeoxyuridine; C059506:moexiprilat; C081643:candesartan