Published Online
on March 21, 2005

A more recent version of this article appeared on March 29, 2005

This Article Full Text (PDF) All Versions of this Article: 111/12/1510    most recent 01.CIR.0000159339.00703.22v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takahashi, H. Articles by Kubota, I. Search for Related Content PubMed PubMed Citation Articles by Takahashi, H. Articles by Kubota, I. Related Collections Cell signalling/signal transduction

Submitted on July 19, 2004
Revised on November 15, 2004
Accepted on November 29, 2004

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, and 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.

^* To whom correspondence should be addressed. E-mail: takeishi{at}med.id.yamagata-u.ac.jp.

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

This article has been cited by other articles:

				S. F. Steinberg Structural Basis of Protein Kinase C Isoform Function Physiol Rev, October 1, 2008; 88(4): 1341 - 1378. [Abstract] [Full Text] [PDF]

				J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger Designing Heart Performance by Gene Transfer Physiol Rev, October 1, 2008; 88(4): 1567 - 1651. [Abstract] [Full Text] [PDF]

				T. Niizeki, Y. Takeishi, T. Kitahara, T. Arimoto, M. Ishino, O. Bilim, S. Suzuki, T. Sasaki, O. Nakajima, R. A. Walsh, et al. Diacylglycerol kinase-{varepsilon} restores cardiac dysfunction under chronic pressure overload: a new specific regulator of G{alpha}q signaling cascade Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H245 - H255. [Abstract] [Full Text] [PDF]

				V. O. Rybin, J. Guo, Z. Gertsberg, S. J. Feinmark, and S. F. Steinberg Phorbol 12-Myristate 13-Acetate-dependent Protein Kinase C{delta}-Tyr311 Phosphorylation in Cardiomyocyte Caveolae J. Biol. Chem., June 27, 2008; 283(26): 17777 - 17788. [Abstract] [Full Text] [PDF]

				C. P. Alibin, M. A. Kopilas, and H. D. I. Anderson Suppression of Cardiac Myocyte Hypertrophy by Conjugated Linoleic Acid: ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS {alpha} AND {gamma} J. Biol. Chem., April 18, 2008; 283(16): 10707 - 10715. [Abstract] [Full Text] [PDF]

				M. Endoh Novel signalling cascade for cardiac hypertrophy activation by uncoupling and internalization of {beta}1-adrenoceptors Cardiovasc Res, April 1, 2008; 78(1): 5 - 7. [Full Text] [PDF]

				T. Arimoto, Y. Takeishi, H. Takahashi, T. Shishido, T. Niizeki, Y. Koyama, R. Shiga, N. Nozaki, O. Nakajima, K. Nishimaru, et al. Cardiac-Specific Overexpression of Diacylglycerol Kinase {zeta} Prevents Gq Protein-Coupled Receptor Agonist-Induced Cardiac Hypertrophy in Transgenic Mice Circulation, January 3, 2006; 113(1): 60 - 66. [Abstract] [Full Text] [PDF]