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Glucocorticoid stimulation increases cardiac contractility by SGK1-dependent SOCE-activation in rat cardiac myocytes


Autoři: Michael Wester aff001;  Anton Heller aff001;  Michael Gruber aff002;  Lars S. Maier aff001;  Christian Schach aff001;  Stefan Wagner aff001
Působiště autorů: University Heart Center Regensburg, University Hospital Regensburg, Regensburg, Germany aff001;  Clinic for Anesthesiology, University Hospital Regensburg, Regensburg, Germany aff002
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0222341

Souhrn

Aims

Glucocorticoid (GC) stimulation has been shown to increase cardiac contractility by elevated intracellular [Ca] but the sources for Ca entry are unclear. This study aims to determine the role of store-operated Ca entry (SOCE) for GC-mediated inotropy.

Methods and results

Dexamethasone (Dex) pretreatment significantly increased cardiac contractile force ex vivo in Langendorff-perfused Sprague-Dawley rat hearts (2 mg/kg BW i.p. Dex 24 h prior to experiment). Moreover, Ca transient amplitude as well as fractional shortening were significantly enhanced in Fura-2-loaded isolated rat ventricular myocytes exposed to Dex (1 mg/mL Dex, 24 h). Interestingly, these Dex-dependent effects could be abolished in the presence of SOCE-inhibitors SKF-96356 (SKF, 2 μM) and BTP2 (5 μM). Ca transient kinetics (time to peak, decay time) were not affected by SOCE stimulation. Direct SOCE measurements revealed a negligible magnitude in untreated myocytes but a dramatic increase in SOCE upon Dex-pretreatment. Importantly, the Dex-dependent stimulation of SOCE could be blocked by inhibition of serum and glucocorticoid-regulated kinase 1 (SGK1) using EMD638683 (EMD, 50 μM). Dex preincubation also resulted in increased mRNA expression of proteins involved in SOCE (stromal interaction molecule 2, STIM2, and transient receptor potential cation channels 3/6, TRPC 3/6), which were also prevented in the presence of EMD.

Conclusion

Short-term GC-stimulation with Dex improves cardiac contractility by a SOCE-dependent mechanism, which appears to involve increased SGK1-dependent expression of the SOCE-related proteins. Since Ca transient kinetics were unaffected, SOCE appears to influence Ca cycling more by an integrated response across multiple cardiac cycles but not on a beat-to-beat basis.

Klíčová slova:

Biology and life sciences – Cell biology – Cellular types – Animal cells – Anatomy – Biological tissue – Calcium channels – Physiology – Electrophysiology – Neurophysiology – Neuroscience – Biochemistry – Proteins – Molecular biology – Molecular biology techniques – Molecular biology assays and analysis techniques – Gene expression and vector techniques – Protein expression – Medicine and health sciences – Muscle tissue – Muscle cells – Cardiomyocytes – Myofibrils – Sarcomeres – Cardiovascular anatomy – Heart – Surgical and invasive medical procedures – Functional electrical stimulation – Physical sciences – Physics – Biophysics – Chemistry – Chemical compounds – Alkaloids – Caffeine – Research and analysis methods


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