Functional role of NFAT in ventricular cardiomyocytes of rat
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Catecholamines contribute to the adaption of heart to pressure overload via stimulation of adrenoceptors (a- or b-adrenoceptor). While mechanisms resulting in hypertrophic growth of myocytes after a- or b-adrenoceptor-stimulation are established, the functional consequences on cardiomyocyte contractility or hypertrophy are unknown. The present study investigates whether a- or b-adrenoceptor-stimulation by phenylephrine (PE) or isoprenaline (ISO) over 24 h modifies cell shortening in ventricular cardiomyocytes of rat. In PE-treated myocytes cell shortening at 0.5 Hz was reduced. At 2.0 Hz this reduction was compensated by an increased relaxation velocity. In parallel, SERCA2A expression was increased at protein level and at mRNA level. This induction was independent of PKC activation but dependent on an increase in diastolic calcium. The calcineurin/NFAT pathway was identified, since addition of BAPTA, cyclosporine or NFAT-decoy oligonucleotides reduced SERCA2A expression in presence of PE as regulators of SERCA2A expression. Inhibition of SERCA up regulation under PE by NFAT decoy oligonucleotides reduced cell shortening at high beating frequencies. Under b-adrenoceptor stimulation similar effects were found: SERCA2A expression was increased under ISO-stimulation and could be reduced to basal level by NFAT decoy oligonucleotides. Decreased cell shortening under ISO is found at 0.5 Hz, but not at high beating frequencies (2 Hz). In myocytes transformed with NFAT decoy oligos decreased cell shortening is present also at 2 Hz under b-adrenergic stimulation. In conclusion, a functional deficite in contraction of cardiomyocytes due to PE or ISO stimulation can be partially antagonized by PE- or ISO-dependent activation of SERCA expression mediated via the calcium/calcineurin/NFAT pathwayVerknüpfung zu Publikationen oder weiteren Datensätzen
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Giessen : VVB Laufersweiler 2006