title: Diacylglycerol kinase ζ inhibits ventricular tachyarrhythmias in a mouse model of heart failure.
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.
  
  
  RESULTS
  Effects of DGKζ on VT using transgenic mice with transient cardiac expression of activated G protein α(q) (Gα(q)-TG; model of HF) were elucidated and double transgenic mice with cardiac-specific overexpression of both DGKζ and the activated Gα(q) (Gα(q)/DGKζ-TG) were used. Premature ventricular contraction (PVC) and/or VT were frequently observed in Gα(q)-TG mice but not in Gα(q)/DGKζ-TG and wild-type (WT) mice (P<0.01). Protein expressions of canonical transient receptor potential (TRPC) channels 3 and 6 increased in Gα(q)-TG hearts compared with WT and Gα(q)/DGKζ-TG hearts. SK&F96365, a TRPC channel blocker, decreased the number of PVC and prevented VT in anesthetized Gα(q)-TG mice (P<0.05). 1-oleoyl-2-acyl-sn-glycerol (OAG), a diacylglycerol analogue, increased the number of PVC in isolated Gα(q)-TG hearts compared with WT hearts and induced VT in Gα(q)-TG hearts (P<0.01). SK&F96365 decreased the number of PVC and prevented VT in isolated Gα(q)-TG hearts (P<0.01) even in the presence of OAG. Early afterdepolarization (EAD)-induced triggered activity was frequently observed in single Gα(q)-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.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Iwate Medical University School of Pharmaceutical Science, Iwate, Japan. mhirose@iwate-med.ac.jp
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirose
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Niizeki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakada
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shimojo
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kashihara
authors.forename: Miwa
authors.initials: M
authors.lastname: Horiuchi-Hirose
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mende
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
mesh_terms: D000818:Animals; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000502:physiology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics; D006333:Heart Failure / Q000150:complications*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac; D050052:TRPC Cation Channels; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000517:prevention & control*; D018879:Ventricular Premature Complexes / Q000209:etiology
chemical_list: D050052:TRPC Cation Channels; D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse; D043802:GTP-Binding Protein alpha Subunits, Gq-G11