BACKGROUND: Significant gender-related differences exist in the development of left ventricular hypertrophy (LVH). In addition, administration of 17beta-estradiol (E2) to ovariectomized female mice attenuates the development of LVH, demonstrating an antagonistic role for E2 in this process, although no molecular mechanism has been proposed for this phenomenon.
METHODS AND RESULTS: E2 attenuated phenylephrine and endothelin-1 induced hypertrophy in neonatal cardiomyocytes, and E2 directly induced atrial natriuretic factor (ANF) expression as assessed by Northern blot, immunocytochemical analyses, and transient transfection assays using ANF promoter deletion fragments. Both the antihypertrophic effects and ANF induction could be blocked by the estrogen receptor antagonist ICI 182,780, which demonstrates a genomic, estrogen receptor-dependent pathway. To mimic E2-induced autocrine/paracrine effects through stimulation of the guanylyl cyclase A receptor (ANF receptor), cardiomyocytes were stimulated with phenylephrine or endothelin-1 in the presence of exogenous ANF or 8-bromo-cyclic guanosine monophosphate (cGMP), both of which attenuated agonist-induced hypertrophy. Both estrogen and ANF increased cGMP activity. The antihypertrophic effect of ANF could be reduced with extracellular ANF antibodies in a dose-dependent manner. cGMP-dependent protein kinase mediates the antihypertrophic effects of E2, so cardiomyocytes were agonist stimulated in the presence of the cGMP-dependent protein kinase blocker KT-5823. KT-5823 not only reversed the antihypertrophic properties of E2, ANF, or 8-bromo-cGMP, but also evoked potentiation of hypertrophy.
CONCLUSIONS: E2-mediated induction of ANF in cardiac hypertrophy contributes to its antagonistic effects in LVH.
|Number of pages
|Published - 20 Jan 2004
- 8-Bromo Cyclic Adenosine Monophosphate/pharmacology
- Atrial Natriuretic Factor/biosynthesis
- Autocrine Communication
- Cell Line
- Cell Size/drug effects
- Cells, Cultured
- Cyclic GMP-Dependent Protein Kinases/metabolism
- Guanylate Cyclase/metabolism
- Heart Ventricles/cytology
- Hypertrophy, Left Ventricular/etiology
- Myocytes, Cardiac/cytology
- Paracrine Communication
- RNA, Messenger/biosynthesis
- Rats, Inbred Lew
- Receptors, Atrial Natriuretic Factor/metabolism