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. 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

Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels

“…Additionally, many studies speculate the potential deleterious effect of SOCs in atrial and ventricular arrhythmias (27, 29, 31, 32). Interestingly, we and others have demonstrated that TRPC dysfunction could be responsible for the occurrence of ventricular tachycardia (27,28). In the current study, we showed a diastolic Ca 2ϩ increase during field stimulation in NRVMs induced by chronic aldosterone treatment.…”

“…Furthermore, SOCE potentially has proarrhythmic effects (27)(28)(29)(30). SKF-96365, a common inhibitor of SOCs, decreased the number of ventricular tachycardia and early afterdepolarization in mouse hearts expressing constitutively active G␣ q with increased TRPC3 and -C6 expression (27).…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Genetic overexpression of Ga q proteins in the mouse causes heart failure and elevated TRPC3 and TRPC6 expression (Hirose et al, 2011). TRPC3 is also upregulated in several animal models of cardiac hypertrophy (see Watanabe et al, 756 Nilius and Szallasi 2013).…”

“…Although the existence of a number of TRP channels (TRPM4 and all TRPCs with the exception of TRPC5) have been reported in SA node cells (see Watanabe et al, 2009;Dietrich and Gudermann, 2011), it is unclear whether any of these channels is involved in the cation conductance that regulates the pacemaker activity. Transgenic mice that overexpress Ga q (a mouse model of heart failure) display premature ventricular contractions that are exacerbated by OAG (1-oleoyl-2-acetyl-sn-glycerol) (Hirose et al, 2011), a DAG analog known to activate a functional subset of TRPC channels, namely TRPC3, TRPC6, and TRPC7 (Venkatachalam et al, 2003). Interestingly, these animals showed increased expression of TRPC3 and TRPC6 in their heart.…”

Activation of Transient Receptor Potential Canonical 3 (TRPC3)-mediated Ca2+ Entry by A1 Adenosine Receptor in Cardiomyocytes Disturbs Atrioventricular Conduction

“…Any alteration of these channels by activation of G protein-coupled receptors (such as ARs) under pathological conditions could affect Ca 2ϩ entry and promote pro-arrhythmic alterations of membrane potential. For instance, activation of TRPC3/6 channels by G␣ q and DAG results in early afterdepolarizations in the failing heart of adult mouse (42).…”