Angiotensin converting enzyme inhibition modulates cardiac fibroblast growth.

in Journal of hypertension (1998), 16(3), 377-84

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 ... [more ▼]

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. [less ▲]

Cardiac myocytes and fibroblasts contain functional estrogen receptors.

in FEBS letters (1997), 416(1), 107-12

Gender-based differences found in cardiovascular diseases raise the possibility that estrogen may have direct effects on cardiac tissue. Therefore we investigated whether cardiac myocytes and fibroblasts ... [more ▼]

Gender-based differences found in cardiovascular diseases raise the possibility that estrogen may have direct effects on cardiac tissue. Therefore we investigated whether cardiac myocytes and fibroblasts express functional estrogen receptors. Immunofluorescence demonstrated estrogen receptor protein expression in both female and male rat cardiac myocytes and fibroblasts. Nuclear translocation of the estrogen receptor protein was observed after stimulation of cardiomyocytes with 17beta-estradiol (E2). Cells transfected with an estrogen-responsive reporter plasmid showed that treatment with E2 induced a significant increase in reporter activity. Furthermore, E2 induced a significant increase in expression of the estrogen receptors alpha and beta, progesterone receptor and connexin 43 in cardiac myocytes. Cardiac myocytes and fibroblasts contain functional estrogen receptors and estrogen regulates expression of specific cardiac genes. These data suggest that gender-based differences in cardiac diseases may in part be due to direct effects of estrogen on the heart. [less ▲]