Published Online
on December 27, 2005

A more recent version of this article appeared on January 3, 2006

This Article Full Text (PDF) All Versions of this Article: 113/1/60    most recent CIRCULATIONAHA.105.560771v1 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 Arimoto, T. Articles by Kubota, I. Search for Related Content PubMed PubMed Citation Articles by Arimoto, T. Articles by Kubota, I.

Submitted on July 20, 2004
Revised on October 6, 2005
Accepted on October 17, 2005

Cardiac-Specific Overexpression of Diacylglycerol Kinase Prevents Gq Protein-Coupled Receptor Agonist-Induced Cardiac Hypertrophy in Transgenic Mice

Takanori Arimoto MD, Yasuchika Takeishi MD^*, Hiroki Takahashi MD, Tetsuro Shishido MD, Takeshi Niizeki MD, Yo Koyama MD, Ryoko Shiga MD, Naoki Nozaki MD, Osamu Nakajima PhD, Kazuhide Nishimaru PhD, Jun-ichi Abe MD, Masao Endoh MD, Richard A. Walsh MD, Kaoru Goto MD, and Isao Kubota MD

From the First Department of Internal Medicine (T.A., Y.T., H.T., T.S., T.N., Y.K., R.S., N.N., I.K.), Research Laboratory for Molecular Genetics (O.N.), Department of Cardiovascular Pharmacology (K.N., M.E.), and Department of Anatomy and Cell Biology (K.G.), Yamagata University School of Medicine, Yamagata, Japan; Center for Cardiovascular Research, University of Rochester, Rochester, NY (J.A.); and Department of Medicine, Case Western Reserve University, Cleveland, Ohio (R.A.W.).

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

Background--Diacylglycerol is a lipid second messenger that accumulates in cardiomyocytes when stimulated by Gq 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.

Methods and Results--To test this hypothesis, we generated transgenic (DGK-TG) mice with cardiac-specific overexpression of DGK. There were no differences in heart size and heart weight between DGK-TG and wild-type littermate mice. The left ventricular function was normal in DGK-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 DGK-TG mice, neither translocation of PKC nor upregulation of atrial natriuretic factor gene expression was observed after angiotensin II and phenylephrine infusion. Furthermore, in DGK-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 DGK-TG mouse hearts, suggesting that DGK regulated PKC activity by controlling cellular diacylglycerol levels.

Conclusions--These results demonstrated the first evidence that DGK negatively regulated the hypertrophic signaling cascade and resultant cardiac hypertrophy in response to GPCR agonists without detectable adverse effects in in vivo hearts.

Key words: angiotensin • hypertrophy • enzymes • signal transduction

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]

				T. Kitahara, Y. Takeishi, M. Harada, T. Niizeki, S. Suzuki, T. Sasaki, M. Ishino, O. Bilim, O. Nakajima, and I. Kubota High-mobility group box 1 restores cardiac function after myocardial infarction in transgenic mice Cardiovasc Res, October 1, 2008; 80(1): 40 - 46. [Abstract] [Full Text] [PDF]

				T. Urashima, M. Zhao, R. Wagner, G. Fajardo, S. Farahani, T. Quertermous, and D. Bernstein Molecular and physiological characterization of RV remodeling in a murine model of pulmonary stenosis Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1351 - H1368. [Abstract] [Full Text] [PDF]

				C. Hu, A. Dandapat, L. Sun, M. R. Marwali, N. Inoue, F. Sugawara, K. Inoue, Y. Kawase, K.-i. Jishage, H. Suzuki, et al. Modulation of Angiotensin II-Mediated Hypertension and Cardiac Remodeling by Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Deletion Hypertension, September 1, 2008; 52(3): 556 - 562. [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. Crotty, J. Cai, F. Sakane, A. Taketomi, S. M. Prescott, and M. K. Topham Diacylglycerol kinase {delta} regulates protein kinase C and epidermal growth factor receptor signaling PNAS, October 17, 2006; 103(42): 15485 - 15490. [Abstract] [Full Text] [PDF]