Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart |
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| Authors: | Sandeep S Hothi Iman S Gurung Jennifer C Heathcote Yanmin Zhang Stephen W Booth Jeremy N Skepper Andrew A Grace Christopher L-H Huang |
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| Institution: | (1) Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK;(2) Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK;(3) Multi-Imaging Centre, University of Cambridge, Cambridge, CB2 3DY, UK |
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| Abstract: | The recently described exchange protein directly activated by cAMP (Epac) has been implicated in distinct protein kinase A-independent cellular signalling pathways. We investigated the role
of Epac activation in adrenergically mediated ventricular arrhythmogenesis. In contrast to observations in control conditions
(n = 20), monophasic action potentials recorded in 2 of 10 intrinsically beating and 5 of 20 extrinsically paced Langendorff-perfused
wild-type murine hearts perfused with the Epac activator 8-pCPT-2′-O-Me-cAMP (8-CPT, 1 μM) showed spontaneous triggered activity.
Three of 20 such extrinsically paced hearts showed spontaneous ventricular tachycardia (VT). Programmed electrical stimulation
provoked VT in 10 of 20 similarly treated hearts (P < 0.001; n = 20). However, there were no statistically significant accompanying changes (P > 0.05) in left ventricular epicardial (40.7 ± 1.2 versus 44.0 ± 1.7 ms; n = 10) or endocardial action potential durations (APD90; 51.8 ± 2.3 versus 51.9 ± 2.2 ms; n = 10), transmural (ΔAPD90) (11.1 ± 2.6 versus 7.9 ± 2.8 ms; n = 10) or apico-basal repolarisation gradients, ventricular effective refractory periods (29.1 ± 1.7 versus 31.2 ± 2.4 ms
in control and 8-CPT-treated hearts, respectively; n = 10) and APD90 restitution characteristics. Nevertheless, fluorescence imaging of cytosolic Ca2+ levels demonstrated abnormal Ca2+ homeostasis in paced and resting isolated ventricular myocytes. Epac activation using isoproterenol in the presence of H-89
was also arrhythmogenic and similarly altered cellular Ca2+ homeostasis. Epac-dependent effects were reduced by Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibition with 1 μM KN-93. These findings associate VT in an intact cardiac
preparation with altered cellular Ca2+ homeostasis and Epac activation for the first time, in the absence of altered repolarisation gradients previously implicated
in reentrant arrhythmias through a mechanism dependent on CaMKII activity. |
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| Keywords: | Epac cAMP Calcium Ventricular arrhythmia Ryanodine receptor CaMKII |
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