Background The Gαq 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 αq subunit in the hearts of transgenic mice (Gαq-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 DGKζ (DGKζ-TG) inhibit GPCR agonist-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy, so this study tested the hypothesis that DGKζcould rescue Gαq-TG mice from developing HF. Methods and Results Double transgenic mice (Gαq/DGKζ-TG) with cardiac-specific overexpression of both DGKζand Gαq were generated by crossing Gαq-TG with DGKζ-TG mice, and the pathophysiological consequences were analyzed. DGKζ 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 Gαq-TG mice. Translocation of PKC isoforms, phosphorylation activity of c-jun N-terminal kinase and p38 mitogen-activated protein kinase in Gαq-TG mice were attenuated by DGKζ. DGKζ improved the survival rate of Gαq-TG mice. Conclusions These results demonstrate the first evidence that DGKζ blocks cardiac dysfunction and progression to lethal HF by activated Gαq protein without detectable adverse effects in the in-vivo heart and suggest that DGKζis a novel therapeutic target for HF. (Circ J 2008; 72: 309 - 317)