Diacylglycerol Kinase ζ Inhibits Ventricular Tachyarrhythmias in a Mouse Model of Heart Failure

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 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.