Cardiac-specific overexpression of diacylglycerol kinase zeta prevents Gq protein-coupled receptor agonist-induced cardiac hypertrophy in transgenic mice.

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.
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.
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.
AuthorsTakanori Arimoto, Yasuchika Takeishi, Hiroki Takahashi, Tetsuro Shishido, Takeshi Niizeki, Yo Koyama, Ryoko Shiga, Naoki Nozaki, Osamu Nakajima, Kazuhide Nishimaru, Jun-ichi Abe, Masao Endoh, Richard A Walsh, Kaoru Goto, Isao Kubota
JournalCirculation (Circulation) Vol. 113 Issue 1 Pg. 60-6 (Jan 3 2006) ISSN: 1524-4539 [Electronic] United States
PMID16380548 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Diglycerides
  • RNA, Messenger
  • Angiotensin II
  • Phenylephrine
  • Diacylglycerol Kinase
  • diacylglycerol kinase zeta, rat
  • Protein Kinase C
  • Ventricular Myosins
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Heterotrimeric GTP-Binding Proteins
  • Angiotensin II (pharmacology)
  • Animals
  • Cardiomegaly (prevention & control)
  • Diacylglycerol Kinase (genetics, pharmacology)
  • Diglycerides (metabolism)
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Heterotrimeric GTP-Binding Proteins (agonists)
  • Mice
  • Mice, Transgenic
  • Myocardium (metabolism, pathology)
  • Myocytes, Cardiac (drug effects, physiology)
  • Phenylephrine (pharmacology)
  • Promoter Regions, Genetic
  • Protein Kinase C (metabolism)
  • RNA, Messenger (analysis)
  • Rats
  • Signal Transduction (drug effects)
  • Ventricular Myosins (genetics)

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