Activation of the calcineurin/NFAT signalling cascade starts early in human hypertrophic myocardium.
Cardiac hypertrophy is an independent risk factor for heart failure. Recent studies on gene regulation of proteins have involved intracellular Ca2+ homeostasis. The Ca2+-sensitive phosphatase, calcineurin, is one potential regulator of the hypertrophic response, so we aimed to investigate the calcineurin-dependent signal pathway at different stages of hypertrophy in human myocardium. We found the calcineurin pathway to be significantly activated in hypertrophic compared with non-hypertrophic myocardium as demonstrated by increased calcineurin activity and expression of calcineurin A-beta and B, and GATA-4, and a shift of phosphorylated cytoplasmic NFAT-3 into the nucleus as dephosphorylated nuclear NFAT-3. There was a tendency for these changes to be more pronounced in the decompensated compared with the compensated hypertrophic myocardium. The present study provides evidence for significant activation of the Ca2+-triggered calcineurin pathway in hypertrophic humans. Already present in compensated hypertrophy it showed a tendency to a further increase following transition to decompensated hypertrophy.
Diedrichs
H
H
Laboratory of Muscle Research and Molecular Cardiology, Department of Internal Medicine, University of Cologne, Cologne, Germany. Holger.Diedrichs@uni-koeln.de
Hagemeister
J
J
Chi
M
M
Boelck
B
B
Müller-Ehmsen
J
J
Schneider
C A
CA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D005260:Female; D050991:GATA4 Transcription Factor / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000502:physiology*
D050991:GATA4 Transcription Factor; D050778:NFATC Transcription Factors; D020033:Protein Isoforms; D019703:Calcineurin; D002118:Calcium