Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Arrhythmia/Electrophysiology
Diacylglycerol Kinase ζ Inhibits Ventricular Tachyarrhythmias in a Mouse Model of Heart Failure
– Roles of Canonical Transient Receptor Potential (TRPC) Channels –
Masamichi HiroseYasuchika TakeishiTakeshi NiizekiTsutomu NakadaHisashi ShimojoToshihide KashiharaMiwa Horiuchi-HiroseIsao KubotaUlrike MendeMitsuhiko Yamada
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2011 Volume 75 Issue 10 Pages 2333-2342

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Abstract

Background: Diacylglycerol kinase ζ (DGKζ) inhibited atrial tachyarrhythmias in a mouse model of heart failure (HF) in our study. However, whether DGKζ prevents the HF-induced ventricular tachyarrhythmia (VT) is unknown. Methods and Results: Effects of DGKζ on VT using transgenic mice with transient cardiac expression of activated G protein αq (Gαq-TG; model of HF) were elucidated and double transgenic mice with cardiac-specific overexpression of both DGKζ and the activated Gαq (Gαq/DGKζ-TG) were used. Premature ventricular contraction (PVC) and/or VT were frequently observed in Gαq-TG mice but not in Gαq/DGKζ-TG and wild-type (WT) mice (P<0.01). Protein expressions of canonical transient receptor potential (TRPC) channels 3 and 6 increased in Gαq-TG hearts compared with WT and Gαq/DGKζ-TG hearts. SK&F96365, a TRPC channel blocker, decreased the number of PVC and prevented VT in anesthetized Gαq-TG mice (P<0.05). 1-oleoyl-2-acyl-sn-glycerol (OAG), a diacylglycerol analogue, increased the number of PVC in isolated Gαq-TG hearts compared with WT hearts and induced VT in Gαq-TG hearts (P<0.01). SK&F96365 decreased the number of PVC and prevented VT in isolated Gαq-TG hearts (P<0.01) even in the presence of OAG. Early afterdepolarization (EAD)-induced triggered activity was frequently observed in single Gαq-TG ventricular myocytes. Moreover, SK&F96365 prevented the EAD. Conclusions: These results demonstrated that DGKζ inhibited VT in a mouse model of HF and suggest that TRPC channels participate in VT induction in failing hearts. (Circ J 2011; 75: 2333-2342)

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© 2011 THE JAPANESE CIRCULATION SOCIETY
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