Effects of moexiprilat on oestrogen-stimulated cardiac fibroblast growth.
1. The effects of 2-2-(1-(ethoxycarbonyl)-3-phenylpropyl)-[amino-oxopropyl]-6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline-3 carboxylic acid (moexiprilat), 17beta-oestradiol (E2), oestrone (ES) and angiotensin II (AII) on growth and activation of oestrogen receptors and the immediate-early gene egr-1 were investigated in neonatal rat cardiac fibroblasts of female and male origin. 2. In BrdU proliferation assays, oestrone (10(-7)- 10(-9) M) stimulated cardiac fibroblast growth in a concentration-dependent fashion (maximum at 10(-7) M, 4.0 fold +/- 0.14 in female and 3.1 fold +/- 0.06 in male cells, n=9, P<0.05), while E2 (10(-7)-10(-9) M) had no effect. Moexiprilat (10(-7)M) completely inhibited oestrone-induced cardiac fibroblast growth. 3. Angiotensin II (10(-7) M) induced cardiac fibroblast growth (female 4.1 fold +/- 0.1/male 3.9 fold +/- 0.2; n=9, P<0.05). Angiotensin II induced oestrogen receptor (maximum 21.8 fold at 60 min) and egr-1 (maximum 47.5 fold at 60 min) expression in a time-dependent fashion. 4. In immunoblot experiments, oestrogen activated oestrogen receptor (ES: 12.8 fold +/- 2.0; E2: 14.7 fold +/- 4.9; n=3, P<0.05) and egr-1 (ES: 5.1 fold, +/- 0.24; E2: 3.8 fold, +/- 0.25; n=3, P<0.05) expression. The induction of oestrogen receptor and egr-1 protein expression was time-dependent and inhibited by moexiprilat. 5. Our results show that oestrone and 17beta-oestradiol reveal a significant difference in their potential to activate cardiac fibroblast growth in female and male cells and that oestrone-stimulated growth is inhibited by moexiprilat. The inhibition of oestrone-stimulated cardiac fibroblast growth by moexiprilat may contribute to the beneficial effects seen in postmenopausal women with hypertensive heart disease treated with ACE inhibitors.
Grohé
C
C
Medizinische Universitäts-Poliklinik, University of Bonn, Germany.
Kahlert
S
S
Lóbbert
K
K
van Eickels
M
M
Stimpel
M
M
Vetter
H
H
Neyses
L
L
D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics; D051766:Early Growth Response Protein 1; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D017874:Immediate-Early Proteins; D015151:Immunoblotting; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics; D044005:Tetrahydroisoquinolines; D014157:Transcription Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D004967:Estrogens; D017874:Immediate-Early Proteins; D007546:Isoquinolines; D015682:Retroviridae Proteins, Oncogenic; D044005:Tetrahydroisoquinolines; D014157:Transcription Factors; D000804:Angiotensin II; C059506:moexiprilat