title: Angiotensin converting enzyme inhibition modulates cardiac fibroblast growth.
abstract: BACKGROUND
  The progression of left ventricular hypertrophy and cardiac fibrosis in hypertensive heart disease is influenced by sex and age. Although angiotensin converting enzyme inhibition has been shown to prevent progression of the disease in postmenopausal women, the interaction of angiotensin II and estrogen in this process before and after the menopause is poorly understood.
  
  
  OBJECTIVE
  To investigate the influence of the angiotensin converting enzyme inhibitor moexiprilat on serum, estrogen and angiotensin II-induced cardiac fibroblast growth.
  
  
  METHODS
  Neonatal rat cardiac fibroblasts were incubated with 1 and 10% fetal calf serum, 10(-7) mol/l angiotensin II, 10(-9) mol/l estrone, 10(-9) mol/l 17beta-estradiol and 10(-8) mol/l moexiprilat. Proliferation was measured in terms of incorporation of bromodeoxyuridine. Western blot analysis was performed using antibodies directed against the growth-related immediate early genes c-fos and Sp-1. All experiments were performed at least three times.
  
  
  RESULTS
  Fetal calf serum stimulated cardiac fibroblast proliferation (1% fetal calf serum 2.0+/-0.028-fold; 10% fetal calf serum 2.7+/-0.028-fold). Angiotensin II and estrone stimulated proliferation of cardiac fibroblasts grown in the absence of fetal calf serum (angiotensin II 4.2+/-0.075-fold; estrone 2.9+/-0.034-fold) and further increased proliferation in the presence of 1% fetal calf serum (angiotensin 11 4.3+/-0.072-fold); estrone 3.8+/-0.045-fold) and 10% fetal calf serum (angiotensin II 4.8+/-0.112-fold; estrone 4.1+/-0.047-fold). Coincubation with moexiprilat specifically inhibited proliferation induced by angiotensin II and estrone but not by serum, and angiotensin II type 1 receptor blockade inhibited angiotensin II-induced but not estrone-induced cell growth. Western blot analysis showed that the expression of c-fos and Sp-1 was induced in a time-dependent fashion by angiotensin II (to maxima of 5.0-fold for c-fos and 3.0-fold for Sp-1) and estrone (15.2-fold for c-fos and 6.2-fold for Sp-1). This effect was completely inhibited by moexiprilat.
  
  
  CONCLUSIONS
  Angiotensin converting enzyme inhibition modulates cardiac fibroblast growth induced by angiotensin II and estrone. This mechanism might contribute to the beneficial effects of angiotensin converting enzyme inhibition in postmenopausal patients with hypertensive heart disease.
authors.affiliation: Medizinische Universitäts-Poliklinik, University of Bonn, Germany. c.grohe@uni.bonn.de
authors.forename: C
authors.initials: C
authors.lastname: Grohé
authors.forename: S
authors.initials: S
authors.lastname: Kahlert
authors.forename: K
authors.initials: K
authors.lastname: Löbbert
authors.forename: L
authors.initials: L
authors.lastname: Neyses
authors.forename: M
authors.initials: M
authors.lastname: van Eickels
authors.forename: M
authors.initials: M
authors.lastname: Stimpel
authors.forename: H
authors.initials: H
authors.lastname: Vetter
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media; D004719:Endomyocardial Fibrosis / Q000209:etiology / Q000517:prevention & control; D004958:Estradiol / Q000494:pharmacology; D004970:Estrone / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000517:prevention & control; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008593:Menopause; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D016329:Sp1 Transcription Factor / Q000235:genetics; D044005:Tetrahydroisoquinolines
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D003470:Culture Media; D007546:Isoquinolines; D016329:Sp1 Transcription Factor; D044005:Tetrahydroisoquinolines; D000804:Angiotensin II; D004970:Estrone; D004958:Estradiol; C059506:moexiprilat