Diacylglycerol kinase zeta attenuates pressure overload-induced cardiac hypertrophy.

Abstract

BACKGROUND:

The Gaq protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in the development of cardiac hypertrophy and heart failure. DAG kinase (DGK) phosphorylates DAG and controls cellular DAG levels, thus acting as a regulator of GPCR signaling. It has been previously reported that DGK inhibited GPCR agonist-induced activation of the DAG-PKC signaling and subsequent cardiomyocyte hypertrophy, so the purpose of this study was to examine whether DGK modifies the development of cardiac hypertrophy induced by pressure overload.

METHODS AND RESULTS:

Thoracic transverse aortic constriction (TAC) was created in transgenic mice with cardiac-specific overexpression of DGKzeta (DGKzeta-TG) and wild-type (WT) mice. Increases in heart weight at 4 weeks after TAC were attenuated in DGKzeta-TG mice compared with WT mice. Increases in interventricular septal thickness, dilatation of the left ventricular cavity, and decreases in left ventricular systolic function in WT mice were observed with echocardiography at 4 weeks after TAC surgery. However, these structural and functional changes after TAC were attenuated in DGKzeta-TG mice. In WT mice, cardiac fibrosis and up-regulation of profibrotic genes, such as transforming growth factor-beta1, collagen type I, and collagen type III, were observed at 4 weeks after TAC. However, cardiac fibrosis and gene induction of type I and type III collagens, but not transforming growth factor-beta1, were blocked in DGKzeta-TG mice.

CONCLUSION:

These results are the first in vivo evidence that DGKzeta suppresses cardiac hypertrophy and fibrosis and prevents impaired left ventricular systolic function caused by pressure overload.

• Authors: Mutsuo Harada, Yasuchika Takeishi, Takanori Arimoto, Takeshi Niizeki, Tatsuro Kitahara, Kaoru Goto, Richard A Walsh, Isao Kubota
• Journal: Circulation journal : official journal of the Japanese Circulation Society (Circ J) Vol. 71 Issue 2 Pg. 276-82 (Feb 2007) ISSN: 1346-9843 [Print] Japan
• PMID: 17251681 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Diacylglycerol Kinase
• diacylglycerol kinase zeta, mouse

Topics

• Animals
• Aorta (physiopathology)
• Cardiomegaly (etiology, prevention & control)
• Constriction, Pathologic (physiopathology)
• Diacylglycerol Kinase (genetics, metabolism)
• Disease Models, Animal
• Echocardiography
• Gene Expression Regulation, Enzymologic (physiology)
• Mice
• Mice, Transgenic
• Myocardium (enzymology, pathology)
• Signal Transduction (physiology)
• Transcriptional Activation
• Ventricular Dysfunction, Left (enzymology, physiopathology, prevention & control)