Abstract
Background: Activation of the diacylglycerol-protein kinase C (DAG-PKC) cascade has been implicated in cardiac dysfunction after ischemia/reperfusion (I/R). DAG kinase (DGK) terminates DAG signaling by converting it to phosphatidic acid, and thus may act as a regulator of DAG-PKC signaling. It has been reported that α, ϵ, and &#03B6; isoforms of DGK have been identified in the heart. We examined the functional role of DGKα in cardiac injury after I/R. Methods and Results: We generated transgenic mice with cardiac specific overexpression of DGKα (DGKα-TG) using α-myosin heavy chain promoter. Left anterior descending coronary artery was transiently occluded for 30 min and reperfused for 24 hr in DGKα-TG and wild type littermate (WT) mice. After 24 hr, echocardiography was performed, mice were sacrificed, and the hearts were removed. Areas at risk and infarct size were assessed by Evans blue/TTC double staining. Left ventricular chamber dilatation after I/R was more pronounced in DGKα-TG mice than in WT mice (left ventricular end-diastolic dimension: 3.44 +/− 0.41 mm vs. 3.05 +/−0.24 mm, P < 0.01). Left ventricular systolic function was more severely depressed in DGKα-TG mice than in WT mice (left ventricular fractional shortening: 34.3 +/− 3.6% vs. 42.2 +/− 4.0%, P < 0.01). The ratio of infarct size/area at risk at 24 hr after I/R was larger in DGKα-TG mice than in WT mice (17.9 +/− 4.2% vs. 11.3 +/− 3.3%, P < 0.01). The phosphorylation activity of extracellular-signal regulated kinase (ERK) was increased after I/R in WT mouse hearts (2.58 +/−0.52-fold increase, P<0.0001). However in DGKα-TG mice, activation of ERK after I/R was abolished (1.77+/−0.67-fold increase, P<0.01 vs. WT). Conclusion: DGKα exacerbates cardiac injury by inhibiting cardio-protective effect of ERK activation.
Published Version
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