Cardiac-specific overexpression of diacylglycerol kinase ξ prevents Gq protein-coupled receptor agonist-induced cardiac hypertrophy in transgenic mice

Background-Diacylglycerol is a lipid second messenger that accumulates in cardiomyocytes when stimulated by Gq alpha 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 sigma-TG) mice with cardiac-specific overexpression of DGK sigma. There were no differences in heart size and heart weight between DGK sigma-TG and wild-type littermate mice. The left ventricular function was normal in DGK sigma-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 sigma-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 sigma-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 sigma-TG mouse hearts, suggesting that DGK sigma regulated PKC activity by controlling cellular diacylglycerol levels. Conclusions-These results demonstrated the first evidence that DGK sigma negatively regulated the hypertrophic signaling cascade and resultant cardiac hypertrophy in response to GPCR agonists without detectable adverse effects in in vivo hearts.