Abstract 559: Diacylglycerol Kinase-ζ Rescues Gαq-induced Heart Failure
Background: 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 heart failure. Thus, 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. DAG kinase (DGK) catalyzes DAG and controls cellular DAG levels, and thus may act as a negative regulator of GPCR signaling. In this study, we tested the hypothesis that DGKζ rescues Gαq-TG mice from developing heart failure.
Methods and Results: We generated double transgenic mice (Gαq/DGKζ-TG) with cardiac-specific overexpression of both DGKζ and constitutive active Gαq by crossing Gαq-TG mice with transgenic mice with cardiac-specific overexpression of DGKζ (DGKζ-TG), and the pathophysiological consequences were analyzed. DGKζ inhibited cardiac hypertrophy and progression to heart failure in Gαq-TG mice (Table⇓). DGKζ prevented dilatation of left ventricular dimension and reduction of left ventricular fractional shortening in Gαq-TG mice. Markedly increased left ventricular end-diastolic pressure in Gαq-TG mice was normalized in Gαq/DGKζ-TG mice. Increases in heart weight/body weight ratio and cardiomyocyte cross sectional area were attenuated in Gαq/DGKζ-TG mice. Translocation of PKC α and ε isoforms, activation of JNK and p38 MAPK induced by Gαq were attenuated by DGKζ. DGKζ reduced fibrotic changes and concomitant upregulation of fibrosis-related genes such as collagen type I and type III induced by Gαq. DGKζ improved the survival rate of Gαq-TG mice.
Conclusions: These results demonstrate the first evidence that DGKζ prevents cardiac dysfunction and heart failure by activated Gαq without detectable adverse effects in in vivo hearts and suggest that DGKζ represents a novel therapeutic target for cardiac hypertrophy and heart failure.