title: Cardiac-specific overexpression of diacylglycerol kinase zeta prevents Gq protein-coupled receptor agonist-induced cardiac hypertrophy in transgenic mice.
abstract: BACKGROUND
  Diacylglycerol is a lipid second messenger that accumulates in cardiomyocytes when stimulated by Gqalpha protein-coupled receptor (GPCR) agonists such as angiotensin II, phenylephrine, and others. Diacylglycerol functions as a potent activator of protein kinase C (PKC) and is catalyzed by diacylglycerol kinase (DGK) to form phosphatidic acid and inactivated. However, the functional roles of DGK have not been previously examined in the heart. We hypothesized that DGK might prevent GPCR agonist-induced activation of diacylglycerol downstream signaling cascades and subsequent cardiac hypertrophy.
  
  
  RESULTS
  To test this hypothesis, we generated transgenic (DGKzeta-TG) mice with cardiac-specific overexpression of DGKzeta. There were no differences in heart size and heart weight between DGKzeta-TG and wild-type littermate mice. The left ventricular function was normal in DGKzeta-TG mice. Continuous administration of subpressor doses of angiotensin II and phenylephrine caused PKC translocation, gene induction of atrial natriuretic factor, and subsequent cardiac hypertrophy in WT mice. However, in DGKzeta-TG mice, neither translocation of PKC nor upregulation of atrial natriuretic factor gene expression was observed after angiotensin II and phenylephrine infusion. Furthermore, in DGKzeta-TG mice, angiotensin II and phenylephrine failed to increase cross-sectional cardiomyocyte areas and heart to body weight ratios. Phenylephrine-induced increases in myocardial diacylglycerol levels were completely blocked in DGKzeta-TG mouse hearts, suggesting that DGKzeta regulated PKC activity by controlling cellular diacylglycerol levels.
  
  
  CONCLUSIONS
  These results demonstrated the first evidence that DGKzeta negatively regulated the hypertrophic signaling cascade and resultant cardiac hypertrophy in response to GPCR agonists without detectable adverse effects in in vivo hearts.
authors.affiliation: First Department of Internal Medicine, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Arimoto
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shishido
authors.forename: Takeshi
authors.initials: T
authors.lastname: Niizeki
authors.forename: Yo
authors.initials: Y
authors.lastname: Koyama
authors.forename: Ryoko
authors.initials: R
authors.lastname: Shiga
authors.forename: Naoki
authors.initials: N
authors.lastname: Nozaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakajima
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Nishimaru
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Abe
authors.forename: Masao
authors.initials: M
authors.lastname: Endoh
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: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000517:prevention & control*; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000494:pharmacology*; D004075:Diglycerides / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins / Q000819:agonists*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D024723:Ventricular Myosins / Q000235:genetics
chemical_list: D004075:Diglycerides; D012333:RNA, Messenger; D000804:Angiotensin II; D010656:Phenylephrine; D019852:Diacylglycerol Kinase; C508008:diacylglycerol kinase zeta, rat; D011493:Protein Kinase C; D024723:Ventricular Myosins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins