17beta-estradiol prevents programmed cell death in cardiac myocytes.

in Biochemical and biophysical research communications (2000), 268(1), 192-200

The cardioprotective effects of estrogens are clearly established. However, the underlying mechanisms are poorly understood. Because programmed cell death (apoptosis) probably contributes to the loss of ... [more ▼]

The cardioprotective effects of estrogens are clearly established. However, the underlying mechanisms are poorly understood. Because programmed cell death (apoptosis) probably contributes to the loss of cardiac myocytes in heart failure and because estrogens prevent apoptosis in breast cancer cells, we investigated whether the loss of cardiac myocytes by programmed cell death could be prevented by physiological doses of 17beta-estradiol. Apoptosis of cultured cardiac myocytes was induced by staurosporine. 17beta-estradiol (10 nM) had an antiapoptotic effect as determined by morphological analysis, vital staining using the Hoechst dye 33342 and terminal transferase dUTP nick-end labeling (TUNEL). As a potential mechanism for the antiapoptotic effect of 17beta-estradiol we found a reduced activity of the ICE-like protease caspase-3 in hormone-treated myocytes. Furthermore, inhibition of apoptosis by estradiol was associated with a reduced activity of NF-kappaB transcription factors, particularly p65/RelA and p50. To our knowledge, these data provide the first indication that 17beta-estradiol in physiological concentrations inhibits apoptosis in cardiac myocytes. The antiapoptotic effect of estrogens might contribute to the known cardioprotective effect of estrogens and provides a starting point for the development of future treatment options. [less ▲]

Effects of moexiprilat on oestrogen-stimulated cardiac fibroblast growth.

in British journal of pharmacology (1997), 121(7), 1350-4

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 ... [more ▼]

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. [less ▲]

Oxygenated sterols and intracellular calcium dynamics - comparison with cholesterol and clinical application

in Beck, J; Crastes de Paulet, A (Eds.) Biological activities of oxygenated sterols (1988)

[Mechanism of action of calcium antagonists].

in Schweizerische Rundschau für Medizin Praxis (1985), 74(19), 483-90

High density lipoproteins--modulators of the calcium channel?

in Journal of Hypertension. Supplement) (1985), 3(3), 49-51

It has recently been shown that human red blood cells possess a voltage-independent calcium channel which can be influenced by in vitro modification of the membraneous cholesterol content. To determine ... [more ▼]

It has recently been shown that human red blood cells possess a voltage-independent calcium channel which can be influenced by in vitro modification of the membraneous cholesterol content. To determine whether there is also a link between plasma lipids and the calcium influx through this channel under in vivo conditions, the calcium influx was measured in red blood cells from 51 male donors (aged 41 +/- 5 years). The influx through the channel was defined as the nitrendipine (15 mumol/l)-inhibitable part of 45Ca2+ influx. The Ca(2+)-ejecting ATPase was inhibited by vanadate. The results demonstrate a strong inverse relationship (r = -0.81; P < 0.001) between the plasma concentration of high density lipoproteins (HDL) and 45Ca2+ influx. No significant correlation was found between 45Ca2+ influx and triglycerides, low density lipoproteins (LDL), very low density lipoproteins (VLDL), total plasma cholesterol or extracellular electrolytes (K+, Na+, Ca2+, Mg2+). The results indicate that HDL are involved in the modulation of the calcium channel and provide a link between the cellular cholesterol turnover and the calcium influx in the pathogenesis of atherosclerosis and hypertension. [less ▲]

The cholesterol content of the human erythrocyte influences calcium influx through the channel.

in Biochemical and biophysical research communications (1984), 124(3), 822-8

In order to study the influence of the cholesterol content on the calcium entry channel, the human red blood cell was used as a model system. The cholesterol to lecithin ratio (C/L ratio) of the membrane ... [more ▼]

In order to study the influence of the cholesterol content on the calcium entry channel, the human red blood cell was used as a model system. The cholesterol to lecithin ratio (C/L ratio) of the membrane was modified experimentally by incubating the cells (15h, 25 degrees) with liposomes of defined C/L ratios. Subsequently, net 45Calcium-influx into the cell was measured by inhibiting the Ca-ejecting ATPase with vanadate. Additionally, the use of nitrendipine, a potent calcium channel inhibitor, during incubation allowed the determination of Ca-influx through the calcium channel. A positive correlation between the 45Ca++-influx and the molar C/L ratio of the membrane was found over a wide C/L range. A molar C/L ratio of 1.4 in the membrane increased calcium influx by 150 % compared to controls (molar C/L ratio = 0.8, calcium influx rate = 100 %), while a molar C/L ratio at less than 0.75 decreased calcium influx by 50 %. We conclude, that the cholesterol content of the membrane greatly influences the calcium channel and thus plays a pivotal role for the availability of calcium as a second messenger. These findings may provide a link between high plasma cholesterol and the development of atherosclerosis as well as enhanced platelet aggregability. [less ▲]

Cholesterol and its oxidized derivatives modulate the calcium channel in human red blood cells.

in Journal of Hypertension. Supplement) (1984), 2(3), 489-92

The human red blood cell was used as a model system in order to study the effect of cholesterol and its medically important oxidized derivatives (OSC = oxidized sterol compounds) on the calcium entry ... [more ▼]

The human red blood cell was used as a model system in order to study the effect of cholesterol and its medically important oxidized derivatives (OSC = oxidized sterol compounds) on the calcium entry channel. The calcium-ejecting adenosine triphosphatase (ATPase) was inhibited by vanadate and the influx of 45Ca2-into the cells measured. The cells were loaded with OSC at concentrations between 0.075 and 1.5 micrograms OSC/10(7) cells. Two classes of OSC could be distinguished: one stimulating Ca2+ influx dose-dependently by almost 100% at maximum concentrations, the other inhibiting it dose-dependently by up to 80%. The calcium channel blocker nitrendipine inhibited influx by 70% at 15 microM. More than 90% of the total stimulation or inhibition was accounted for by an influence on the nitrendipine-inhibitable part of influx, i.e. the calcium channel. Cholesterol (incorporated using liposomes) had a stimulatory (+288%), cholesterol depletion an inhibitory effect on calcium influx (-18%). These results demonstrate that cholesterol and its oxidized derivatives modulate the calcium channel in a highly stereospecific manner and provide new insights into the mechanism of action and the atherogenic effect of these compounds. [less ▲]