Ferron L.,Remodelage Tissulaire et Fonctionnel Signalisation et Physiopathologie |
Ferron L.,University College London |
Ruchon Y.,Remodelage Tissulaire et Fonctionnel Signalisation et Physiopathologie |
Ruchon Y.,University Paris - Sud |
And 4 more authors.
Cardiovascular Research | Year: 2011
Aims We have investigated Ca2+ signalling generated by aldosterone-induced T-type current (ICaT), the effects of I CaT in neonatal cardiomyocytes, and a putative role for I CaT in cardiomyocytes during cardiac pathology induced by stenosis in an adult rat. Methods and resultsNeonatal rat cardiomyocytes treated with aldosterone showed an increase in ICaT density, principally due to the upregulation of the T-type channel Cav3.1 (by 80). Aldosterone activated cAMP-response element-binding protein (CREB), and this activation was enhanced by blocking ICaT or by inhibiting protein phosphatase 2A (PP2A) activity. Aldosterone induced PP2A activity, an induction that was prevented upon ICaT blockade. ICaT exerted a negative feedback regulation on the transcription of the Cav3.1 gene, and the activation of PP2A by ICaT led to increased levels of the pro-apoptotic markers caspase 9 and Bcl-xS and decreased levels of the anti-apoptotic marker Bcl-2. These findings were corroborated by flow cytometry analysis for apoptosis and necrosis. Similarly, in a rat model of cardiac disease, ICaT re-emergence was associated with a decrease in CREB activation and was correlated with increases in caspase 9 and Bcl-xS and a decrease in Bcl-2 levels. Conclusion Our findings establish PP2A/CREB as targets of ICaT-generated Ca2+ signalling and identify an important role for ICaT in cardiomyocyte cell death. © 2010 The Author.