Adenovirus-mediated overexpression of diacylglycerol kinase-ζ inhibits endothelin-1-induced cardiomyocyte hypertrophy

Hiroki Takahashi, Yasuchika Takeishi, Tim Seidler, Takanori Arimoto, Hideyuki Akiyama, Yasukazu Hozumi, Yo Koyama, Tetsuro Shishido, Yuichi Tsunoda, Takeshi Niizeki, Naoki Nozaki, Jun Ichi Abe, Gerd Hasenfuss, Kaoru Goto, Isao Kubota

Research output: Contribution to journalArticle

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Abstract

Background - Diacylglycerol (DAG) is a lipid second messenger that transiently accumulates in cells stimulated by endothelin-1 (ET-1) and other Gαq protein-coupled receptor agonists. Diacylglycerol kinase (DGK) is thought to be an enzyme that controls the cellular levels of DAG by converting it to phosphatidic acid; however, the functional role of DGK has not been examined in cardiomyocytes. Because DGK inactivates DAG, a strong activator of protein kinase C (PKC), we hypothesized that DGK inhibited ET-1-induced activation of a DAG-PKC signaling cascade and subsequent cardiomyocyte hypertrophy. Methods and Results - Real-time reverse transcription-polymerase chain reaction demonstrated a significant increase of DGK-ζ mRNA by ET-1 in cardiomyocytes. To determine the functional role of DGK-ζ, we overexpressed DGK-ζ in cardiomyocytes using a recombinant adenovirus encoding rat DGK-ζ (Ad-DGKζ). ET-1-induced translocation of PKC-ε was blocked by Ad-DGKζ (P<0.01). Ad-DGKζ also inhibited ET-1-induced activation of extracellular signal-regulated kinase (P<0.01). Luciferase reporter assay revealed that ET-1-mediated increase of activator protein-1 (AP1) DNA-binding activity was significantly inhibited by DGK-ζ (P<0.01). In cardiomyocytes transfected with DGK-ζ, ET-1 failed to cause gene induction of atrial natriuretic factor, increases in [3H]- leucine uptake, and increases in cardiomyocyte surface area. Conclusions - We demonstrated for the first time that DGK-ζ blocked ET-1-induced activation of the PKC-ε-ERK-AP1 signaling pathway, atrial natriuretic factor gene induction, and resultant cardiomyocyte hypertrophy. DGK-ζ might act as a negative regulator of hypertrophic program in response to ET-1, possibly by controlling cellular DAG levels.

Original languageEnglish (US)
Pages (from-to)1510-1516
Number of pages7
JournalCirculation
Volume111
Issue number12
DOIs
StatePublished - Mar 29 2005

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Diacylglycerol Kinase
Endothelin-1
Cardiac Myocytes
Adenoviridae
Hypertrophy
Diglycerides
Protein Kinase C
Transcription Factor AP-1
Atrial Natriuretic Factor
Gq-G11 GTP-Binding Protein alpha Subunits
Phosphatidic Acids

Keywords

  • Endothelin
  • Enzymes
  • Hypertrophy
  • Proteins
  • Signal transduction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Takahashi, H., Takeishi, Y., Seidler, T., Arimoto, T., Akiyama, H., Hozumi, Y., ... Kubota, I. (2005). Adenovirus-mediated overexpression of diacylglycerol kinase-ζ inhibits endothelin-1-induced cardiomyocyte hypertrophy. Circulation, 111(12), 1510-1516. https://doi.org/10.1161/01.CIR.0000159339.00703.22

Adenovirus-mediated overexpression of diacylglycerol kinase-ζ inhibits endothelin-1-induced cardiomyocyte hypertrophy. / Takahashi, Hiroki; Takeishi, Yasuchika; Seidler, Tim; Arimoto, Takanori; Akiyama, Hideyuki; Hozumi, Yasukazu; Koyama, Yo; Shishido, Tetsuro; Tsunoda, Yuichi; Niizeki, Takeshi; Nozaki, Naoki; Abe, Jun Ichi; Hasenfuss, Gerd; Goto, Kaoru; Kubota, Isao.

In: Circulation, Vol. 111, No. 12, 29.03.2005, p. 1510-1516.

Research output: Contribution to journalArticle

Takahashi, H, Takeishi, Y, Seidler, T, Arimoto, T, Akiyama, H, Hozumi, Y, Koyama, Y, Shishido, T, Tsunoda, Y, Niizeki, T, Nozaki, N, Abe, JI, Hasenfuss, G, Goto, K & Kubota, I 2005, 'Adenovirus-mediated overexpression of diacylglycerol kinase-ζ inhibits endothelin-1-induced cardiomyocyte hypertrophy', Circulation, vol. 111, no. 12, pp. 1510-1516. https://doi.org/10.1161/01.CIR.0000159339.00703.22
Takahashi, Hiroki ; Takeishi, Yasuchika ; Seidler, Tim ; Arimoto, Takanori ; Akiyama, Hideyuki ; Hozumi, Yasukazu ; Koyama, Yo ; Shishido, Tetsuro ; Tsunoda, Yuichi ; Niizeki, Takeshi ; Nozaki, Naoki ; Abe, Jun Ichi ; Hasenfuss, Gerd ; Goto, Kaoru ; Kubota, Isao. / Adenovirus-mediated overexpression of diacylglycerol kinase-ζ inhibits endothelin-1-induced cardiomyocyte hypertrophy. In: Circulation. 2005 ; Vol. 111, No. 12. pp. 1510-1516.
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T1 - Adenovirus-mediated overexpression of diacylglycerol kinase-ζ inhibits endothelin-1-induced cardiomyocyte hypertrophy

AU - Takahashi, Hiroki

AU - Takeishi, Yasuchika

AU - Seidler, Tim

AU - Arimoto, Takanori

AU - Akiyama, Hideyuki

AU - Hozumi, Yasukazu

AU - Koyama, Yo

AU - Shishido, Tetsuro

AU - Tsunoda, Yuichi

AU - Niizeki, Takeshi

AU - Nozaki, Naoki

AU - Abe, Jun Ichi

AU - Hasenfuss, Gerd

AU - Goto, Kaoru

AU - Kubota, Isao

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N2 - Background - Diacylglycerol (DAG) is a lipid second messenger that transiently accumulates in cells stimulated by endothelin-1 (ET-1) and other Gαq protein-coupled receptor agonists. Diacylglycerol kinase (DGK) is thought to be an enzyme that controls the cellular levels of DAG by converting it to phosphatidic acid; however, the functional role of DGK has not been examined in cardiomyocytes. Because DGK inactivates DAG, a strong activator of protein kinase C (PKC), we hypothesized that DGK inhibited ET-1-induced activation of a DAG-PKC signaling cascade and subsequent cardiomyocyte hypertrophy. Methods and Results - Real-time reverse transcription-polymerase chain reaction demonstrated a significant increase of DGK-ζ mRNA by ET-1 in cardiomyocytes. To determine the functional role of DGK-ζ, we overexpressed DGK-ζ in cardiomyocytes using a recombinant adenovirus encoding rat DGK-ζ (Ad-DGKζ). ET-1-induced translocation of PKC-ε was blocked by Ad-DGKζ (P<0.01). Ad-DGKζ also inhibited ET-1-induced activation of extracellular signal-regulated kinase (P<0.01). Luciferase reporter assay revealed that ET-1-mediated increase of activator protein-1 (AP1) DNA-binding activity was significantly inhibited by DGK-ζ (P<0.01). In cardiomyocytes transfected with DGK-ζ, ET-1 failed to cause gene induction of atrial natriuretic factor, increases in [3H]- leucine uptake, and increases in cardiomyocyte surface area. Conclusions - We demonstrated for the first time that DGK-ζ blocked ET-1-induced activation of the PKC-ε-ERK-AP1 signaling pathway, atrial natriuretic factor gene induction, and resultant cardiomyocyte hypertrophy. DGK-ζ might act as a negative regulator of hypertrophic program in response to ET-1, possibly by controlling cellular DAG levels.

AB - Background - Diacylglycerol (DAG) is a lipid second messenger that transiently accumulates in cells stimulated by endothelin-1 (ET-1) and other Gαq protein-coupled receptor agonists. Diacylglycerol kinase (DGK) is thought to be an enzyme that controls the cellular levels of DAG by converting it to phosphatidic acid; however, the functional role of DGK has not been examined in cardiomyocytes. Because DGK inactivates DAG, a strong activator of protein kinase C (PKC), we hypothesized that DGK inhibited ET-1-induced activation of a DAG-PKC signaling cascade and subsequent cardiomyocyte hypertrophy. Methods and Results - Real-time reverse transcription-polymerase chain reaction demonstrated a significant increase of DGK-ζ mRNA by ET-1 in cardiomyocytes. To determine the functional role of DGK-ζ, we overexpressed DGK-ζ in cardiomyocytes using a recombinant adenovirus encoding rat DGK-ζ (Ad-DGKζ). ET-1-induced translocation of PKC-ε was blocked by Ad-DGKζ (P<0.01). Ad-DGKζ also inhibited ET-1-induced activation of extracellular signal-regulated kinase (P<0.01). Luciferase reporter assay revealed that ET-1-mediated increase of activator protein-1 (AP1) DNA-binding activity was significantly inhibited by DGK-ζ (P<0.01). In cardiomyocytes transfected with DGK-ζ, ET-1 failed to cause gene induction of atrial natriuretic factor, increases in [3H]- leucine uptake, and increases in cardiomyocyte surface area. Conclusions - We demonstrated for the first time that DGK-ζ blocked ET-1-induced activation of the PKC-ε-ERK-AP1 signaling pathway, atrial natriuretic factor gene induction, and resultant cardiomyocyte hypertrophy. DGK-ζ might act as a negative regulator of hypertrophic program in response to ET-1, possibly by controlling cellular DAG levels.

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