Estrogen inhibits cardiomyocyte hypertrophy in vitro. Antagonism of calcineurin-related hypertrophy through induction of MCIP1.
Evidence from in vivo studies suggests that some inputs to cardiac hypertrophy are opposed by the actions of estrogen. However, the mechanisms of E2 action in this respect are mainly unknown. An important pathway that is utilized by multiple hypertrophic stimuli involves the activation of the tyrosine phosphatase, calcineurin (PP2B). Here we show that 17beta-estradiol (E2) significantly prevents angiotensin II (AngII)- or endothelin-1 (ET-1)-induced new protein synthesis, skeletal muscle actin expression, and increased surface area in cultured rat cardiomyocytes. ET-1 stimulated calcineurin phosphatase activity, resulting in new protein synthesis, and both were prevented by E2. E2 induced the MCIP1 gene, an inhibitor of calcineurin activity, via phosphatidylinositol 3-kinase, transcriptional, and mRNA stability mechanisms. Small interfering RNA for MCIP1 significantly reversed both the E2 restraint of protein synthesis and the inhibition of AngII-induced calcineurin activity. AngII-induced the translocation of the hypertrophic transcription factor, NF-AT, to the nucleus of the cardiomyocyte and stimulated NF-AT transcriptional activity. Both were prevented by E2. AngII also stimulated the activation of ERK and protein kinase C, contributing to cardiac hypertrophy. E2 inhibited these pathways, related to the stimulation of atrial natriuretic peptide production and secretion. Thus, restraint of calcineurin and kinase signaling to the hypertrophic program underlie these important effects of E2.
Pedram
Ali
A
Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, California 90822, USA.
Razandi
Mahnaz
M
Aitkenhead
Mark
M
Levin
Ellis R
ER
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D019703:Calcineurin / Q000378:metabolism / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D019332:Endothelin-1 / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006984:Hypertrophy; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000737:chemistry; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009124:Muscle Proteins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic
D000804:Angiotensin II; D019703:Calcineurin; D004268:DNA-Binding Proteins; D019332:Endothelin-1; D004958:Estradiol; D004967:Estrogens; D048049:Extracellular Signal-Regulated MAP Kinases; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine; D009124:Muscle Proteins; D019001:Nitric Oxide Synthase; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; C108612:RCAN1 protein, human