HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/H245    most recent 00066.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Niizeki, T. Articles by Kubota, I. Search for Related Content PubMed PubMed Citation Articles by Niizeki, T. Articles by Kubota, I.

Diacylglycerol kinase- restores cardiac dysfunction under chronic pressure overload: a new specific regulator of G_q signaling cascade

¹Department of Cardiology, Pulmonology, and Nephrology, ²Research Laboratory for Molecular Genetics, and ³Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata, and ⁴First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan; and ⁵Department of Medicine, Case Western Reserve University, Cleveland, Ohio

Submitted 22 January 2008 ; accepted in final form 13 May 2008

G_q protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in cardiac hypertrophy. DAG kinase (DGK) catalyzes DAG phosphorylation and controls cellular DAG levels, thus acting as a regulator of GPCR signaling. It has been reported that DGK acts specifically on DAG produced by inositol cycling. In this study, we examined whether DGK prevents cardiac hypertrophy and progression to heart failure under chronic pressure overload. We generated transgenic mice with cardiac-specific overexpression of DGK (DGK-TG) using an -myosin heavy chain promoter. There were no differences in cardiac morphology and function between wild-type (WT) and DGK-TG mice at the basal condition. Either continuous phenylephrine infusion or thoracic transverse aortic constriction (TAC) was performed in WT and DGK-TG mice. Increases in heart weight after phenylephrine infusion and TAC were abolished in DGK-TG mice compared with WT mice. Cardiac dysfunction after TAC was prevented in DGK-TG mice, and the survival rate after TAC was higher in DGK-TG mice than in WT mice. Phenylephrine- and TAC-induced DAG accumulation, the translocation of PKC isoforms, and the induction of fetal genes were blocked in DGK-TG mouse hearts. The upregulation of transient receptor potential channel (TRPC)-6 expression after TAC was attenuated in DGK-TG mice. In conclusion, these results demonstrate the first evidence that DGK restores cardiac dysfunction and improves survival under chronic pressure overload by controlling cellular DAG levels and TRPC-6 expression. DGK may be a novel therapeutic target to prevent cardiac hypertrophy and progression to heart failure.

hypertrophy; heart failure; diacylglycerol; protein kinase C