T-type Ca2+ signalling regulates aldosterone-induced CREB activation and cell death through PP2A activation in neonatal cardiomyocytes

Abstract

AimsWe have investigated Ca2+ signalling generated by aldosterone-induced T-type current (ICaT), the effects of ICaT in neonatal cardiomyocytes, and a putative role for ICaT 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.ConclusionOur findings establish PP2A/CREB as targets of ICaT-generated Ca2+ signalling and identify an important role for ICaT in cardiomyocyte cell death.

Lentiviral-mediated p38 MAPK RNAi attenuates aldosterone-induced myocyte apoptosis

“…Previous studies have demonstrated that aldosterone directly induces myocyte apoptosis in a dose-and time-dependent manner (11,12). Our results showed that aldo- (10 -5 mol/l for 24 h) significantly increased the level of myocyte apoptosis.…”

“…Several mechanisms which may link aldosterone and apoptosis have been suggested, including the activation of the membrane receptor-mediated calcineurin-Bad, c-Jun N-terminal kinase (JNK) and ERK1/2 pathways (11)(12)(13). However, whether the mechanism of aldosterone-mediated apoptosis in cardiac myocytes involves the p38 mitogen-activated protein kinase (p38 MAPK) pathway remains controversial.…”

Ppp2ca knockout in mice spermatogenesis

“…For instance, decreased Ppp2ca expression has been associated with Alzheimer's disease and other tauopathies (Planel et al 2007, Whittington et al 2011, which indicates that it plays a role in regulating phosphorylation in the brain. In addition, PP2A was shown to play a role in cardiomyocyte cell death by regulating calcium ion (Ca 2C ) signaling (Ferron et al 2011). Further investigations are necessary to determine the importance of Ppp2ca gene function in other organs.…”

Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels

“…Accumulated evidence suggests that modulation of Ca 2ϩ flux is a central factor in the cardiac MR action and might be involved in triggering after depolarization-related fatal ventricular tachyarrhythmia (34 -39). In addition, aldosterone-mediated cardiac action may cause various responses associated with elevation of [Ca 2ϩ ] i , including the direct or indirect increase of the Ca 2ϩ -dependent phosphatase 2B calcineurin and its downstream transcription factor NFATc3 in the development of cardiac hypertrophy (40), the negative feedback on cAMP-response element-binding protein via protein phosphatase 2A in promoting apoptosis (41), and more recently the activation of the multifunctional Ca 2ϩ / calmodulin-dependent protein kinase II associated with poor outcomes after myocardial infarction (42).…”