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

Bilim, Olga; Takeishi, Yasuchika; Kitahara, Tatsuro; Arimoto, Takanori; Niizeki, Takeshi; Sasaki, Toshiki; Goto, Kaoru; Kubota, Isao
January 2008
Cardiovascular Diabetology;2008, Vol. 7, p1
Academic Journal
Background: 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 PKC� attenuates insulin-stimulated Akt phosphorylation. Methods and Results: We examined transgenic mice with cardiac-specific overexpression of DGK? (DGK?-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 DGK?-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 DGK?-TG mice. Thinning of the interventricular septum and the posterior wall in diabetic WT hearts were blocked in DGK?-TG mice. Reduction of transverse diameter of cardiomyocytes isolated from the left ventricle in diabetic WT mice was attenuated in DGK?-TG mice. Cardiac fibrosis was much less in diabetic DGK?-TG than in diabetic WT mice. Western blots showed translocation of PKC� and d isoforms to membrane fraction and decreased Akt/PKB phosphorylation in diabetic WT mouse hearts. However in diabetic DGK?-TG mice, neither translocation of PKC nor changes Akt/PKB phosphorylation was observed. Conclusion: DGK? modulates intracellular signaling and improves the course of diabetic cardiomyopathy. These data may suggest that DGK? is a new therapeutic target to prevent or reverse diabetic cardiomyopathy.


Related Articles

  • Calcium-dependent Protein Kinase Reactions Associated with Parotid Gland Secretory Granule Membranes. DOWD, F.; WATSON, E. L.; LAU, Y. -S.; JUSTIN, J.; PASIENIUK, J.; JACOBSON, K. L. // Journal of Dental Research;Feb1987, Vol. 66 Issue 2, p557 

    Rat parotid secretary granule membranes were examined for the presence of calcium-dependent protein kinase activities and kinase substrates. Protein kinase C (C-kinase), which is stimulated by certain phospholipids, was present in the membranes, as indicated by its ability to catalyze the...

  • Knockdown of Stat3 activity in vivo prevents diabetic glomerulopathy. Ting-Chi Lu; Zhao-Hui Wang; Xiaobei Feng; Chuang, Peter Y.; Wei Fang; Yuhong Shen; Levy, David E.; Huabao Xiong; Nan Chen; He, John Cijiang // Kidney International;Jul2009, Vol. 76 Issue 1, p63 

    Recent studies suggest that Stat3, a transcription factor that mediates cytokine signaling, plays a critical role in the pathogenesis of diabetic nephropathy. Complete Stat3 gene knockout is embryonic lethal; therefore, we crossed Stat3+/− mice with Stat3 mutant mice (SA/SA) that lack full...

  • TRB3 Gene Silencing Alleviates Diabetic Cardiomyopathy in a Type 2 Diabetic Rat Model. Yun Ti; Guo-lu Xie; Zhi-hao Wang; Xiao-lei Bi; Wen-yuan Ding; Jia Wang; Gui-hua Jiang; Pei-li Bu; Yun Zhang; Ming Zhong; Wei Zhang // Diabetes;Nov2011, Vol. 60 Issue 11, p2963 

    OBJECTIVE--Tribbles 3 (TRB3) is associated with insulin resistance, an important trigger in the development of diabetic cardiomyopathy (DCM). We sought to determine whether TRB3 plays a major role in modulating DCM and the mechanisms involved. RESEARCH DESIGN AND METHODS--The type 2 diabetic rat...

  • Endothelin Signalling in the Cardiac Myocyte and its Pathophysiological Relevance. Sugden, Peter H.; Clerk, Angela // Current Vascular Pharmacology;Oct2005, Vol. 3 Issue 4, p343 

    Endothelin A (ETA) transmembrane receptors predominate in rat cardiac myocytes. These are G proteincoupled receptors whose actions are mediated by the Gq heterotrimeric G proteins. Through these, ET-1 binding to ETAreceptors stimulates the hydrolysis of membrane phosphatidylinositol...

  • The Ca2+-independent PKC (p105) mediates the PMA-activation of marine mussel hemocytes and the Ca2+-dependent PKC (p60) does not intervene. M. Gonzalez-Riopedre; R. Barcia; J. Ramos-Martínez // Molecular & Cellular Biochemistry;Dec2009, Vol. 332 Issue 1/2, p243 

    Abstract  Previous works revealed the presence of a Ca2+-dependent protein kinase (p60) and a Ca2+-independent protein kinase (p105) in the mantle tissue from the sea mussel Mytilus galloprovincialis Lmk. The expression of both isoforms shows a balance between cytosolic and membrane...

  • PKC-dependent Phosphorylation of the H1 Histamine Receptor Modulates TRPC6 Activity. Xingjuan Chen; Egly, Christian; Riley, Ashley M.; Wennan Li; Tewson, Paul; Hughes, Thomas E.; Quinn, Anne Marie; Obukhov, Alexander G. // Cells (2073-4409);Jun2014, Vol. 3 Issue 2, p247 

    Transient receptor potential canonical 6 (TRPC6) is a cation selective, DAG-regulated, Ca2+-permeable channel activated by the agonists of Gq-protein-coupled heptahelical receptors. Dysfunctions of TRPC6 are implicated in the pathogenesis of various cardiovascular and kidney conditions such as...

  • Crystal structure of the integral membrane diacylglycerol kinase. Li, Dianfan; Lyons, Joseph A.; Pye, Valerie E.; Vogeley, Lutz; Aragão, David; Kenyon, Colin P.; Shah, Syed T. A.; Doherty, Christine; Aherne, Margaret; Caffrey, Martin // Nature;5/23/2013, Vol. 497 Issue 7450, p521 

    Diacylglycerol kinase catalyses the ATP-dependent phosphorylation of diacylglycerol to phosphatidic acid for use in shuttling water-soluble components to membrane-derived oligosaccharide and lipopolysaccharide in the cell envelope of Gram-negative bacteria. For half a century, this 121-residue...

  • MK2 Deletion in Mice Prevents Diabetes-Induced Perturbations in Lipid Metabolism and Cardiac Dysfunction. Ruiz, Matthieu; Coderre, Lise; Lachance, Dominic; Houde, Valérie; Martel, Cécile; Legault, Julie Thompson; Gillis, Marc-Antoine; Bouchard, Bertrand; Daneault, Caroline; Carpentier, André C.; Gaestel, Matthias; Allen, Bruce G.; Des Rosiers, Christine; Thompson Legault, Julie // Diabetes;Feb2016, Vol. 65 Issue 2, p381 

    Heart disease remains a major complication of diabetes, and the identification of new therapeutic targets is essential. This study investigates the role of the protein kinase MK2, a p38 mitogen-activated protein kinase downstream target, in the development of diabetes-induced cardiomyopathy....

  • Hot lips and phosphorylation of protein kinases. Marshall, C.J. // Nature;2/24/1994, Vol. 367 Issue 6465, p686 

    Reports on the solution of the protein kinase structure of the mammaliam MAP kinase ERK2. Mechanism of MAP kinase activation; Regulation of kinases by phosphorylation.


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics