Diacylglycerol kinase zeta inhibits G(alpha)q-induced atrial remodeling in transgenic mice.

Abstract

BACKGROUND:

Our previous study showed that diacylglycerol kinase zeta (DGKzeta), which degenerates diacylglycerol (DAG), inhibits ventricular structural remodeling and rescues activated G protein (alpha)q (G(alpha)q)-induced heart failure. However, whether DGKzeta inhibits atrial remodeling is still unknown.

OBJECTIVE:

This study aimed to elucidate the effects of DGKzeta on atrial remodeling.

METHODS:

A transgenic mouse (G(alpha)q-TG) with cardiac expression of activated G(alpha)q and a double transgenic mouse (G(alpha)q/DGKzeta-TG) with cardiac overexpression of DGKzeta and activated G(alpha)q were created.

RESULTS:

During electrocardiogram (ECG) recording for 10 min, atrial fibrillation was observed in 5 of 11 anesthetized G(alpha)q-TG mice but not in any wild-type (WT) and G(alpha)q/DGKzeta-TG mice (P <.05). All of the ECG parameters measured were prolonged in the G(alpha)q-TG compared with WT mice. Interestingly, in G(alpha)q/DGKzeta-TG mice, although the PR and RR intervals were still prolonged, the P interval, QRS complex, and QT interval were not different from those in WT mice. In Langendorff-perfused hearts, the incidence of atrial tachyarrhythmia induced by rapid atrial pacing was greater in G(alpha)q-TG hearts than in G(alpha)q/DGKzeta-TG hearts (P <.05). Action potential duration prolongation and impulse conduction slowing were observed in G(alpha)q-TG atria compared with G(alpha)q/DGKzeta-TG atria. Dilatation of the left atrium with thrombus formation was observed in 9 G(alpha)q-TG hearts but not in any G(alpha)q/DGKzeta-TG hearts. Moreover, the degree of extensive interstitial fibrosis in the left atrium was greater in G(alpha)q-TG hearts than that in G(alpha)q/DGKzeta-TG hearts (P <.05).

CONCLUSION:

These results show that DGKzeta inhibits G(alpha)q-induced atrial remodeling and suggest that DGKzeta is a novel therapeutic target for atrial fibrillation.

• Authors: Masamichi Hirose, Yasuchika Takeishi, Takeshi Niizeki, Hisashi Shimojo, Tsutomu Nakada, Isao Kubota, Jun Nakayama, Ulrike Mende, Mitsuhiko Yamada
• Journal: Heart rhythm (Heart Rhythm) Vol. 6 Issue 1 Pg. 78-84 (Jan 2009) ISSN: 1556-3871 [Electronic] United States
• PMID: 19121805 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Diacylglycerol Kinase
• GTP-Binding Protein alpha Subunits, Gq-G11

Topics

• Animals
• Atrial Fibrillation (drug therapy, metabolism, physiopathology)
• Diacylglycerol Kinase (pharmacology)
• Disease Progression
• Electrocardiography
• Fibrosis
• GTP-Binding Protein alpha Subunits, Gq-G11 (biosynthesis)
• Heart Atria (metabolism, pathology, physiopathology)
• Heart Rate
• Mice
• Mice, Transgenic
• Signal Transduction (drug effects)