title: Diacylglycerol kinase zeta rescues G alpha q-induced heart failure in transgenic mice.
abstract: BACKGROUND
  The G alpha q protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in the development of cardiac hypertrophy and heart failure (HF). It has been reported that the expression of a constitutively active mutant of the G protein alpha q subunit in the hearts of transgenic mice (G alpha q-TG) induces cardiac hypertrophy and lethal HF. DAG kinase (DGK) catalyzes DAG and controls its cellular levels, thus acting as a regulator of GPCR signaling. It has been found that transgenic mice with cardiac-specific overexpression of DGK zeta (DGK zeta-TG) inhibit GPCR agonist-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy, so this study tested the hypothesis that DGK zeta could rescue G alpha q-TG mice from developing HF.
  
  
  RESULTS
  Double transgenic mice (G alpha q/DGK zeta-TG) with cardiac-specific overexpression of both DGK zeta and G alpha q were generated by crossing G alpha q-TG with DGK zeta-TG mice, and the pathophysiological consequences were analyzed. DGK zeta prevented cardiac dysfunction, determined by dilatation of left ventricular (LV) dimensions, reduction of LV fractional shortening, and marked increases in LV end-diastolic pressure in G alpha q-TG mice. Translocation of PKC isoforms, phosphorylation activity of c-jun N-terminal kinase and p38 mitogen-activated protein kinase in G alpha q-TG mice were attenuated by DGK zeta. DGK zeta improved the survival rate of G alpha q-TG mice.
  
  
  CONCLUSIONS
  These results demonstrate the first evidence that DGK zeta blocks cardiac dysfunction and progression to lethal HF by activated G alpha q protein without detectable adverse effects in the in-vivo heart and suggest that DGK zeta is a novel therapeutic target for HF.
authors.affiliation: Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
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: Yo
authors.initials: Y
authors.lastname: Koyama
authors.forename: Kaoru
authors.initials: K
authors.lastname: Goto
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mende
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D043562:Receptors, G-Protein-Coupled; D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse; D011493:Protein Kinase C; D043802:GTP-Binding Protein alpha Subunits, Gq-G11