Diacylglycerol kinase ζ inhibits myocardial atrophy and restores cardiac dysfunction in streptozotocin-induced diabetes mellitus

<p>Abstract</p> <p>Background</p> <p>Activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway has been implicated in the pathogenesis of a number of diabetic complications. Diacylglycerol kinase (DGK) converts DAG to phosphatidic acid and acts as an endogenous regulator of PKC activity. Akt/PKB is associated with a downstream insulin signaling, and PKCβ attenuates insulin-stimulated Akt phosphorylation.</p> <p>Methods and Results</p> <p>We examined transgenic mice with cardiac-specific overexpression of DGKζ (DGKζ-TG) compared to wild type (WT) mice in streptozotocin-induced (STZ, 150 mg/kg) diabetic and nondiabetic conditions. After 8 weeks, decreases in heart weight and heart weight/body weight ratio in diabetic WT mice were inhibited in DGKζ-TG mice. Echocardiography at 8 weeks after STZ-injection demonstrated that decreases in left ventricular end-diastolic diameter and fractional shortening observed in WT mice were attenuated in DGKζ-TG mice. Thinning of the interventricular septum and the posterior wall in diabetic WT hearts were blocked in DGKζ-TG mice. Reduction of transverse diameter of cardiomyocytes isolated from the left ventricle in diabetic WT mice was attenuated in DGKζ-TG mice. Cardiac fibrosis was much less in diabetic DGKζ-TG than in diabetic WT mice. Western blots showed translocation of PKCβ and δ isoforms to membrane fraction and decreased Akt/PKB phosphorylation in diabetic WT mouse hearts. However in diabetic DGKζ-TG mice, neither translocation of PKC nor changes Akt/PKB phosphorylation was observed.</p> <p>Conclusion</p> <p>DGKζ modulates intracellular signaling and improves the course of diabetic cardiomyopathy. These data may suggest that DGKζ is a new therapeutic target to prevent or reverse diabetic cardiomyopathy.</p

Differential regulation of diacylglycerol kinase isoform in human failing hearts

Evidence from several studies indicates the importance of Gαq protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG), and protein kinase C, in the development of heart failure. DAG kinase (DGK) acts as an endogenous regulator of GPCR signaling pathway by catalyzing and regulating DAG. Expressions of DGK isoforms α, ε, and ζ in rodent hearts have been detected; however, the expression and alteration of DGK isoforms in a failing human heart has not yet been examined. In this study, we detected mRNA expressions of DGK isoforms γ, η, ε, and ζ in failing human heart samples obtained from patients undergoing cardiovascular surgery with cardiopulmonary bypass. Furthermore, we investigated modulation of DGK isoform expression in these hearts. We found that expressions of DGKη and DGKζ were increased and decreased, respectively, whereas those of DGKγ and DGKε remained unchanged. This is the first report that describes the differential regulation of DGK isoforms in normal and failing human hearts

Histological analyses in WT and DGKζ-TG mice at 8 weeks after injection of STZ or citrate buffer solution

Hematoxylin-eosin micrographs showing transverse sections of left ventricular myocardium (× 400, bar = 50 μm). Quantitative analysis of cardiomyocyte cross-sectional area (left bar graph) in WT (grey bars) and DGKζ-TG (black bars) mice. Data were calculated by averaging the measurements at least of 100 cardiomyocytes from each sections. Data were obtained from 8 mice for each group.<p><b>Copyright information:</b></p><p>Taken from "Diacylglycerol kinase ζ inhibits myocardial atrophy and restores cardiac dysfunction in streptozotocin-induced diabetes mellitus"</p><p>http://www.cardiab.com/content/7/1/2</p><p>Cardiovascular Diabetology 2008;7():2-2.</p><p>Published online 4 Feb 2008</p><p>PMCID:PMC2265681.</p><p></p

Representative immunoblots of left ventricular extracts with anti- phosphospecific Akt/PKB antibody (upper gel) in WT and DGKζ-TG mice at 8 weeks after injection of STZ or citrate buffer solution

The abundance of Akt protein was demonstrated by immunoblots with an antibody to total Akt (lower gel). Densitometric analyses of Akt phosphorylation were performed using 8 mice for each group. *P < 0.01 vs. WT control, †P < 0.01 vs. WT STZ.<p><b>Copyright information:</b></p><p>Taken from "Diacylglycerol kinase ζ inhibits myocardial atrophy and restores cardiac dysfunction in streptozotocin-induced diabetes mellitus"</p><p>http://www.cardiab.com/content/7/1/2</p><p>Cardiovascular Diabetology 2008;7():2-2.</p><p>Published online 4 Feb 2008</p><p>PMCID:PMC2265681.</p><p></p

Representative Western blots of PKC-α (A), -β (B), -ε (C), and -δ (D) isoforms in membrane and cytosol fractions and densitometric analysis in WT (grey bars) and DGKζ-TG (black bars) mice at 8 weeks after injection of STZ or citrate buffer solution

Membrane/cytosol ratios of immunoreactivity were used as indices of the extent of PKC isoform translocation. We detected that STZ-induced diabetes caused an increase in the membrane/cytosol ratio of PKC-β and -δ isoforms in WT mouse hearts. However in DGKζ-TG mice, translocation of PKC-β and -δ isoforms was significantly attenuated. Data were obtained from 6 mice for each group. *P < 0.05, **P < 0.01 vs. WT control, †P < 0.01 vs. WT STZ.<p><b>Copyright information:</b></p><p>Taken from "Diacylglycerol kinase ζ inhibits myocardial atrophy and restores cardiac dysfunction in streptozotocin-induced diabetes mellitus"</p><p>http://www.cardiab.com/content/7/1/2</p><p>Cardiovascular Diabetology 2008;7():2-2.</p><p>Published online 4 Feb 2008</p><p>PMCID:PMC2265681.</p><p></p