Diacylglycerol kinase α exacerbates cardiac injury after ischemia/reperfusion.

Early coronary reperfusion of the ischemic myocardium is a desired therapeutic goal for the preservation of myocardial function. However, reperfusion itself causes additional myocardium injuries. Activation of the diacylglycerol-protein kinase C (DAG-PKC) cascade has been implicated in the cardioprotective effects occurring after ischemia/reperfusion (I/R). DAG kinase (DGK) controls cellular DAG levels by converting DAG to phosphatidic acid, and may act as an endogenous regulator of DAG-PKC signaling. In the present study, we examined the functional role of DGKα in cardiac injury after I/R in in vivo mouse hearts. We generated transgenic mice with cardiac-specific overexpression of DGKα (DGKα-TG). The left anterior descending coronary artery was transiently occluded for 20 min and reperfused for 24 h in DGKα-TG mice and wild-type littermate (WT) mice. The levels of phosphorylation activity of PKCε, extracellular-signal regulated kinase (ERK) 1/2, and p70 ribosomal S6 kinase (p70S6K) were increased after I/R in WT mouse hearts. However, in DGKα-TG mice, activation of PKCε, ERK1/2, and p70S6K was attenuated compared to WT mice. After 24 h, Evans blue/triphenyltetrazolium chloride double staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining showed that DGKα-TG mice had significantly larger myocardial infarctions and larger numbers of TUNEL-positive cardiomyocytes than WT mice. Echocardiography and cardiac catheterization revealed that left ventricular systolic function was more severely depressed in DGKα-TG mice than in WT mice after I/R. These findings suggest that DGKα exacerbates I/R injury by inhibiting the cardioprotective effects of PKCε, ERK1/2, and p70S6K activation.
AuthorsToshiki Sasaki, Tetsuro Shishido, Shinpei Kadowaki, Tatsuro Kitahara, Satoshi Suzuki, Shigehiko Katoh, Akira Funayama, Shunsuke Netsu, Tetsu Watanabe, Kaoru Goto, Yasuchika Takeishi, Isao Kubota
JournalHeart and vessels (Heart Vessels) Vol. 29 Issue 1 Pg. 110-8 (Jan 2014) ISSN: 1615-2573 [Electronic] Japan
PMID23719772 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Prkce protein, mouse
  • Diacylglycerol Kinase
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Protein Kinase C-epsilon
  • Mapk1 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Animals
  • Apoptosis
  • Diacylglycerol Kinase (genetics, metabolism)
  • Disease Models, Animal
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 1 (metabolism)
  • Mitogen-Activated Protein Kinase 3 (metabolism)
  • Myocardial Infarction (enzymology, genetics, pathology, physiopathology)
  • Myocardial Reperfusion Injury (enzymology, genetics, pathology, physiopathology)
  • Myocardium (enzymology)
  • Phosphorylation
  • Protein Kinase C-epsilon (metabolism)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
  • Signal Transduction
  • Systole
  • Ventricular Function, Left
  • Ventricular Pressure

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