Cardiac-specific overexpression of diacylglycerol kinase ζ attenuates left ventricular remodeling and improves survival after myocardial infarction

Abstract

Left ventricular (LV) remodeling, including cardiomyocyte necrosis, scar formation, LV geometric changes, and cardiomyocyte hypertrophy, contributes to cardiac dysfunction and mortality after myocardial infarction (MI). Although precise cellular signaling mechanisms for LV remodeling are not fully elucidated, G(q) protein-coupled receptor signaling pathway, including diacylglycerol (DAG) and PKC, are involved in this process. DAG kinase (DGK) phosphorylates DAG and controls cellular DAG levels, thus acting as a negative regulator of PKC and subsequent cellular signaling. We previously reported that DGK inhibited angiotensin II and phenylephrine-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy. The purpose of this study was to examine whether DGK modifies LV remodeling after MI. Left anterior descending coronary artery was ligated in transgenic mice with cardiac-specific overexpression of DGKzeta (DGKzeta-TG) and wild-type (WT) mice. LV chamber dilatation (4.12 +/- 0.10 vs. 4.53 +/- 0.32 mm, P < 0.01), reduction of LV systolic function (34.8 +/- 8.3% vs. 28.3 +/- 4.8%, P < 0.01), and increases in LV weight (95 +/- 3.6 vs. 111 +/- 4.1 mg, P < 0.05) and lung weight (160 +/- 15 vs. 221 +/- 25 mg, P < 0.05) at 4 wk after MI were attenuated in DGKzeta-TG mice compared with WT mice. In the noninfarct area, fibrosis fraction (0.51 +/- 0.04, P < 0.01) and upregulation of profibrotic genes, such as transforming growth factor-beta1 (P < 0.01), collagen type I (P < 0.05), and collagen type III (P < 0.01), were blocked in DGKzeta-TG mice. The survival rate at 4 wk after MI was higher in DGKzeta-TG mice than in WT mice (61% vs. 37%, P < 0.01). In conclusion, these results demonstrate the first evidence that DGKzeta suppresses LV structural remodeling and fibrosis and improves survival after MI. DGKzeta may be a potential novel therapeutic target to prevent LV remodeling after MI.