PKC-independent signal transduction pathways increase SERCA2 expression in adult rat cardiomyocytes

Catecholamines seem to play a major role in the initial response of the heart to pressure overload. The mechanisms by which α 1A-adrenoceptor stimulation increases protein synthesis and subsequently cell size have been worked out in the past. However, little is known about the functional consequence...

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Veröffentlicht in:Journal of molecular and cellular cardiology 2005-12, Vol.39 (6), p.911-919
Hauptverfasser: Anwar, Attia, Taimor, Gerhild, Korkususz, Hüdayi, Schreckenberg, Rolf, Berndt, Tobias, Abdallah, Yaser, Piper, Hans Michael, Schlüter, Klaus-Dieter
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container_end_page 919
container_issue 6
container_start_page 911
container_title Journal of molecular and cellular cardiology
container_volume 39
creator Anwar, Attia
Taimor, Gerhild
Korkususz, Hüdayi
Schreckenberg, Rolf
Berndt, Tobias
Abdallah, Yaser
Piper, Hans Michael
Schlüter, Klaus-Dieter
description Catecholamines seem to play a major role in the initial response of the heart to pressure overload. The mechanisms by which α 1A-adrenoceptor stimulation increases protein synthesis and subsequently cell size have been worked out in the past. However, little is known about the functional consequence of this type of hypertrophy. Recent transgenic work seems to indicate an adaptive character of this response, but mechanistic insights have yet to be established. The present study investigates whether chronic (overnight) exposure of cardiomyocytes to phenylephrine, an α-adrenoceptor agonist, modifies the expression of calcium-handling proteins and identifies key elements of signal transduction pathways leading to such alterations. Cardiomyocytes exposed to phenylephrine had elevated expression of SR-calcium ATPase (SERCA), but not of the sodium–calcium exchanger (NCX). SERCA induction persisted in the presence of protein kinase C (PKC) inhibitors, but required an increase in diastolic cell calcium levels via activation of the sodium–proton exchanger (NHE) and the reverse mode of the NCX. Downstream of an increase in resting cell calcium concentrations an activation of the calcineurin/NFAT pathway was found to be responsible for SERCA2 induction. Transfection of cardiomyocytes with decoys directed against NFAT activity inhibited the increase in SERCA2 expression. Decoys did not inhibit the concomitant PKC-dependent increase in hypertrophic growth. In the absence of SERCA up-regulation, hypertrophied cardiomyocytes were unable to maintain normal, load-free cell shortening. In conclusion, our data give mechanistic insights into the adaptional process during α-adrenoceptor-dependent myocardial hypertrophy.
doi_str_mv 10.1016/j.yjmcc.2005.08.001
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The mechanisms by which α 1A-adrenoceptor stimulation increases protein synthesis and subsequently cell size have been worked out in the past. However, little is known about the functional consequence of this type of hypertrophy. Recent transgenic work seems to indicate an adaptive character of this response, but mechanistic insights have yet to be established. The present study investigates whether chronic (overnight) exposure of cardiomyocytes to phenylephrine, an α-adrenoceptor agonist, modifies the expression of calcium-handling proteins and identifies key elements of signal transduction pathways leading to such alterations. Cardiomyocytes exposed to phenylephrine had elevated expression of SR-calcium ATPase (SERCA), but not of the sodium–calcium exchanger (NCX). SERCA induction persisted in the presence of protein kinase C (PKC) inhibitors, but required an increase in diastolic cell calcium levels via activation of the sodium–proton exchanger (NHE) and the reverse mode of the NCX. Downstream of an increase in resting cell calcium concentrations an activation of the calcineurin/NFAT pathway was found to be responsible for SERCA2 induction. Transfection of cardiomyocytes with decoys directed against NFAT activity inhibited the increase in SERCA2 expression. Decoys did not inhibit the concomitant PKC-dependent increase in hypertrophic growth. In the absence of SERCA up-regulation, hypertrophied cardiomyocytes were unable to maintain normal, load-free cell shortening. 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subjects Adrenergic alpha-Agonists - pharmacology
Animals
Calcineurin
Calcium Signaling - drug effects
Calcium-Transporting ATPases - biosynthesis
Cell shortening
Gene Expression Regulation - drug effects
Male
Myocytes, Cardiac - metabolism
NFAT
NHE
Phenylephrine - pharmacology
Protein Biosynthesis - drug effects
Protein Kinase C - antagonists & inhibitors
Protein Kinase C - metabolism
Protein Kinase Inhibitors - pharmacology
Rats
Rats, Wistar
Receptors, Adrenergic - metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases
title PKC-independent signal transduction pathways increase SERCA2 expression in adult rat cardiomyocytes
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