title: Diacylglycerol kinase α exacerbates cardiac injury after ischemia/reperfusion.
abstract: 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.
authors.affiliation: Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iidanishi, Yamagata, 9909585, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Sasaki
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shishido
authors.forename: Shinpei
authors.initials: S
authors.lastname: Kadowaki
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kitahara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Shigehiko
authors.initials: S
authors.lastname: Katoh
authors.forename: Akira
authors.initials: A
authors.lastname: Funayama
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Netsu
authors.forename: Tetsu
authors.initials: T
authors.lastname: Watanabe
authors.forename: Kaoru
authors.initials: K
authors.lastname: Goto
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
mesh_terms: D000818:Animals; D017209:Apoptosis; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology*; D010766:Phosphorylation; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D013599:Systole; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: C497256:Prkce protein, mouse; D019852:Diacylglycerol Kinase; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D051744:Protein Kinase C-epsilon; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3