Abstract 207: Diacylglycerol Kinase-ϵ Prevents Cardiac Hypertrophy Induced By Continuous Administration of Phenylephrine: A New Specific Regulator of Gqα Signaling Cascade
Background: Gqα protein-coupled receptor (GPCR) signaling pathway plays an important role in cardiac hypertrophy and heart failure. Diacylglycerol (DAG) is a lipid second messenger that accumulates in cardiomyocytes when stimulated by GPCR agonists such as angiotensin II, phenylephrine (PE), and others. DAG functions as a strong activator of protein kinase C (PKC) and is catalyzed by DAG kinase (DGK) to form phosphatidic acid and inactivated. We previously found that DGK-ζ inhibited the hypertrophic signaling and resultant cardiac hypertrophy in response to GPCR agonists. Whereas, it has been reported that DGK-ϵ acts specifically on DAG produced by inositol cycling compared to DGK-ζ, suggesting differences in two DGK isoforms about substrate specificity and functional roles in signal transduction. In this study, we generated transgenic mice (DGKϵ-TG) with cardiac-specific overexpression of DGK-ϵ using an alpha-myosin heavy chain (MHC) promoter, and examined whether DGK-ϵ prevents PE-induced activation of DAG downstream signaling.
Methods and Results: Protein level of DGK-ϵ was 25-fold in DGKϵ-TG compared to wild-type (WT) mice. There were no differences in appearance, heart size, and left ventricular function determined by echocardiography between DGKϵ-TG and WT mice at basal condition. Continuous administration of PE caused translocation of PKC α and ϵ and induction of fetal genes such as atrial natriuretic factor (ANF) and β-MHC in WT mice. However in DGKϵ-TG mice, neither translocation of PKC α and ϵ nor re-expression of ANF and β-MHC was observed. Increases in heart / body weight ratio and left ventricle / body weight ratio by PE infusion were abolished in DGKϵ-TG compared to WT mice (Table⇓).
Conclusion: These results demonstrate the first evidence that DGK-ϵ blocks PE-induced hypertrophic signaling and resultant cardiac hypertrophy without detectable adverse effects in vivo. DGK-ϵ may be one of new therapeutic targets to prevent cardiac hypertrophy.