Essential role of ryanodine receptor 2 phosphorylation in the effect of azumolene on ventricular arrhythmia vulnerability in a rabbit heart model

Autor:	Patrick F.H. Lai, John Asta, Mahmoud M. Bokhari, Mohammed Ali Azam, Andreu Porta-Sánchez, Stéphane Massé, Nima Zamiri, Galina Kichigina, Daoyuan Si, Ping Yang, Kumaraswamy Nanthakumar, Christopher Labos, Huan Sun
Rok vydání:	2018
Předmět:	Male 0301 basic medicine medicine.medical_specialty Resuscitation Ischemia chemistry.chemical_element 030204 cardiovascular system & hematology Calcium Ryanodine receptor 2 03 medical and health sciences 0302 clinical medicine Western blot Physiology (medical) Internal medicine medicine Animals Phosphorylation Oxazoles medicine.diagnostic_test business.industry Ryanodine receptor Imidazoles Isolated Heart Preparation Ryanodine Receptor Calcium Release Channel medicine.disease 3. Good health Disease Models Animal Treatment Outcome 030104 developmental biology chemistry Ventricular Fibrillation Ventricular fibrillation cardiovascular system Cardiology Rabbits Cardiology and Cardiovascular Medicine business
Zdroj:	Journal of Cardiovascular Electrophysiology. 29:1707-1715
ISSN:	1540-8167 1045-3873
Popis:	Introduction Following long-duration ventricular fibrillation (LDVF), reinitiation of ventricular fibrillation (VF) poses a major challenge during resuscitation. Ryanodine receptor 2 (RyR2) becomes dysfunctional following VF. The relationship between LDVF, RyR2 modulation, and ventricular refibrillation, as well as the role of RyR2 phosphorylation, remains unknown. Methods Langendorff-perfused rabbit hearts were subjected to global ischemia and treated with azumolene (or vehicle alone in controls) upon reperfusion. After electrical induction of an initial LDVF episode, each heart was further stimulated electrically to assess reinducibility of VF. Myocardial calcium dynamics were assessed by optical mapping. RyR2 phosphorylation in left ventricular tissue extracts was analyzed by Western blot analysis. Results Fewer episodes of refibrillation (lasting ≥ 10 seconds) were induced in azumolene-treated hearts than in controls (P = 0.01); however, this reduction in refibrillation was abrogated in the presence of the protein kinase A inhibitor H89. Spontaneous calcium elevation was significantly lower in azumolene-treated hearts than in control hearts ( P = 0.002) and in hearts pretreated with H89 before azumolene ( P = 0.01). RyR2 phosphorylation at Ser2808 was higher in hearts subjected to LDVF than in non-VF hearts ( P = 0.029), while no significant difference was found at Ser2814. Pretreatment with H89 led to significantly less RyR2 phosphorylation at Ser2808 ( P = 0.04) after LDVF, while pretreatment with KN93 or azumolene alone showed no effects on RyR2 phosphorylation. Conclusion Ventricular refibrillation following LDVF was reduced by azumolene, which also improves calcium dynamics. RyR2 phosphorylation at Ser2808 is a prerequisite for the beneficial effects of azumolene.
Databáze:	OpenAIRE
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