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Differential effects of 17beta-estradiol on mitogen-activated protein kinase pathways in rat cardiomyocytes
S Nuedling1, S Kahlert, K Loebbert
1Medizinische Poliklinik, University of Bonn, Germany.
Abstract:
Cardiac myocytes contain functional estrogen receptors, however, the effect of estrogen on growth-related signaling pathways such as mitogen-activated protein kinases (MAPK) in the pathogenesis of cardiac disease is unclear. MAPKs are critically involved in regulatory signaling pathways which ultimately lead to cardiac hypertrophy. Here we show that 17beta-estradiol (E2) activates extracellular signal-regulated kinase (ERK1/2), c-Jun-NH2-terminal protein kinase (JNK) and p38 in rat cardiomyocytes in a distinctive pattern. As shown by immunoblot analysis and phosphorylation assays, E2 (10(-9) M) induced a rapid and transient activation of ERK1/2 and a rapid but sustained increase of JNK phosphorylation. In contrast, E2 had only a marginal effect on p38 activation. Furthermore, MAPK phosphatase expression was induced by E2 and E2-stimulated expression of endothelial and inducible NO synthase was inhibited by PD 98059, an inhibitor of the ERK pathway. These novel observations may help to explain the role of estrogen in gender-based differences found in cardiac disease.
Insights
Estrogen (E2) activates specific mitogen-activated protein kinases (MAPK) pathways, including ERK1/2 and JNK, in heart cells. This finding clarifies estrogen's role in cardiac disease and gender-based differences.
Area of Science:
- Cardiovascular Biology
- Endocrinology
- Molecular Cell Biology
Background:
- Estrogen receptors are present in cardiac myocytes, but their impact on growth signaling pathways like MAPK in heart disease is not fully understood.
- Mitogen-activated protein kinases (MAPK) are crucial in signaling pathways leading to cardiac hypertrophy.
Purpose of the Study:
- To investigate the effect of 17beta-estradiol (E2) on MAPK activation in rat cardiomyocytes.
- To elucidate the role of estrogen in gender-specific cardiac disease mechanisms.
Main Methods:
- Immunoblot analysis and phosphorylation assays were used to detect MAPK activation.
- The study utilized rat cardiomyocytes and 17beta-estradiol (E2) at a concentration of 10(-9) M.
- Inhibitors like PD 98059 were employed to assess pathway interactions.
Main Results:
- 17beta-estradiol (E2) rapidly and transiently activated extracellular signal-regulated kinase (ERK1/2).
- E2 induced a rapid, sustained increase in c-Jun-NH2-terminal protein kinase (JNK) phosphorylation, with minimal effect on p38.
- E2 upregulated MAPK phosphatase expression, and PD 98059 inhibited E2-stimulated nitric oxide synthase expression.
Conclusions:
- Estrogen differentially activates specific MAPK pathways (ERK1/2, JNK) in cardiomyocytes.
- Estrogen's influence on MAPK signaling may contribute to gender-based differences observed in cardiac disease pathogenesis.
- These findings provide novel insights into the molecular mechanisms underlying estrogen's cardiovascular effects.