Diacylglycerol kinase zeta rescues G alpha q-induced heart failure in transgenic mice.

Abstract

BACKGROUND:

The G alpha q 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 (HF). It has been reported that the expression of a constitutively active mutant of the G protein alpha q subunit in the hearts of transgenic mice (G alpha q-TG) induces cardiac hypertrophy and lethal HF. DAG kinase (DGK) catalyzes DAG and controls its cellular levels, thus acting as a regulator of GPCR signaling. It has been found that transgenic mice with cardiac-specific overexpression of DGK zeta (DGK zeta-TG) inhibit GPCR agonist-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy, so this study tested the hypothesis that DGK zeta could rescue G alpha q-TG mice from developing HF.

METHODS AND RESULTS:

Double transgenic mice (G alpha q/DGK zeta-TG) with cardiac-specific overexpression of both DGK zeta and G alpha q were generated by crossing G alpha q-TG with DGK zeta-TG mice, and the pathophysiological consequences were analyzed. DGK zeta prevented cardiac dysfunction, determined by dilatation of left ventricular (LV) dimensions, reduction of LV fractional shortening, and marked increases in LV end-diastolic pressure in G alpha q-TG mice. Translocation of PKC isoforms, phosphorylation activity of c-jun N-terminal kinase and p38 mitogen-activated protein kinase in G alpha q-TG mice were attenuated by DGK zeta. DGK zeta improved the survival rate of G alpha q-TG mice.

CONCLUSIONS:

These results demonstrate the first evidence that DGK zeta blocks cardiac dysfunction and progression to lethal HF by activated G alpha q protein without detectable adverse effects in the in-vivo heart and suggest that DGK zeta is a novel therapeutic target for HF.

• Authors: Takeshi Niizeki, Yasuchika Takeishi, Tatsuro Kitahara, Takanori Arimoto, Yo Koyama, Kaoru Goto, Ulrike Mende, Isao Kubota
• Journal: Circulation journal : official journal of the Japanese Circulation Society (Circ J) Vol. 72 Issue 2 Pg. 309-17 (Feb 2008) ISSN: 1346-9843 [Print] Japan
• PMID: 18219172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, G-Protein-Coupled
• Diacylglycerol Kinase
• diacylglycerol kinase zeta, mouse
• Protein Kinase C
• GTP-Binding Protein alpha Subunits, Gq-G11

Topics

• Animals
• Cardiomegaly (enzymology, genetics, pathology)
• Diacylglycerol Kinase (genetics, metabolism)
• Disease Models, Animal
• GTP-Binding Protein alpha Subunits, Gq-G11 (genetics, metabolism)
• Heart Failure (enzymology, genetics, pathology)
• Mice
• Mice, Transgenic
• Myocardium (enzymology, pathology)
• Organ Specificity (genetics)
• Protein Kinase C (genetics, metabolism)
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Signal Transduction