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(Circulation. 2006;113:60-66.)
© 2006 American Heart Association, Inc.

Heart Failure

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; 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.).

Reprint requests 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 20, 2004; de novo received May 10, 2005; revision received October 6, 2005; accepted October 17, 2005.

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

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