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(Circulation. 2005;111:1510-1516.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Adenovirus-Mediated Overexpression of Diacylglycerol Kinase- Inhibits Endothelin-1–Induced Cardiomyocyte Hypertrophy

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

From First Department of Internal Medicine (H.T., Y. Takeishi, T.A., H.A., Y.K., T. Shishido, Y. Tsunoda, T.N., N.N., I.K.) and Department of Anatomy and Cell Biology (H.A., Y.H., K.G.), Yamagata University School of Medicine, Yamagata, Japan; Department of Cardiology and Pneumology (T. Seidler, G.H.), Georg-August-University Goettingen, Goettingen, Germany; and Center for Cardiovascular Research (J.A.), University of Rochester, Rochester, NY.

Correspondence to Yasuchika Takeishi, MD, First Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, Japan 990-9585. E-mail takeishi{at}med.id.yamagata-u.ac.jp

Received July 19, 2004; revision received November 15, 2004; accepted November 29, 2004.

Background— Diacylglycerol (DAG) is a lipid second messenger that transiently accumulates in cells stimulated by endothelin-1 (ET-1) and other Gq 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- mRNA by ET-1 in cardiomyocytes. To determine the functional role of DGK-, we overexpressed DGK- in cardiomyocytes using a recombinant adenovirus encoding rat DGK- (Ad-DGK). ET-1–induced translocation of PKC- was blocked by Ad-DGK (P<0.01). Ad-DGK 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- (P<0.01). In cardiomyocytes transfected with DGK-, 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- blocked ET-1–induced activation of the PKC-–ERK-AP1 signaling pathway, atrial natriuretic factor gene induction, and resultant cardiomyocyte hypertrophy. DGK- might act as a negative regulator of hypertrophic program in response to ET-1, possibly by controlling cellular DAG levels.

Key Words: signal transduction • hypertrophy • enzymes • proteins • endothelin

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