title: Diacylglycerol kinase-epsilon restores cardiac dysfunction under chronic pressure overload: a new specific regulator of Galpha(q) signaling cascade.
abstract: Galpha(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 DGKepsilon acts specifically on DAG produced by inositol cycling. In this study, we examined whether DGKepsilon prevents cardiac hypertrophy and progression to heart failure under chronic pressure overload. We generated transgenic mice with cardiac-specific overexpression of DGKepsilon (DGKepsilon-TG) using an alpha-myosin heavy chain promoter. There were no differences in cardiac morphology and function between wild-type (WT) and DGKepsilon-TG mice at the basal condition. Either continuous phenylephrine infusion or thoracic transverse aortic constriction (TAC) was performed in WT and DGKepsilon-TG mice. Increases in heart weight after phenylephrine infusion and TAC were abolished in DGKepsilon-TG mice compared with WT mice. Cardiac dysfunction after TAC was prevented in DGKepsilon-TG mice, and the survival rate after TAC was higher in DGKepsilon-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 DGKepsilon-TG mouse hearts. The upregulation of transient receptor potential channel (TRPC)-6 expression after TAC was attenuated in DGKepsilon-TG mice. In conclusion, these results demonstrate the first evidence that DGKepsilon restores cardiac dysfunction and improves survival under chronic pressure overload by controlling cellular DAG levels and TRPC-6 expression. DGKepsilon may be a novel therapeutic target to prevent cardiac hypertrophy and progression to heart failure.
authors.affiliation: Dept. of Cardiology, Pulmonology, and Nephrology, Yamagata Univ. School of Medicine, Yamagata, Japan. tniizeki@nihonkai.gr.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Niizeki
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kitahara
authors.forename: Takanori
authors.initials: T
authors.lastname: Arimoto
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Ishino
authors.forename: Olga
authors.initials: O
authors.lastname: Bilim
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Toshiki
authors.initials: T
authors.lastname: Sasaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakajima
authors.forename: Richard A
authors.initials: RA
authors.lastname: Walsh
authors.forename: Kaoru
authors.initials: K
authors.lastname: Goto
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000601:surgery; D015153:Blotting, Western; D006332:Cardiomegaly / Q000139:chemically induced / Q000150:complications / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D007527:Isoenzymes; D008026:Ligation; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009929:Organ Size; D010656:Phenylephrine; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D016277:Ventricular Function, Left
chemical_list: D004075:Diglycerides; D005326:Fetal Proteins; D007527:Isoenzymes; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D010656:Phenylephrine; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D043802:GTP-Binding Protein alpha Subunits, Gq-G11