Increased expression of H11 kinase stimulates glycogen synthesis in the heart.
OBJECTIVE
H11 kinase is a serine/threonine kinase preferentially expressed in the heart, which participates in cardiac cell growth and also in cytoprotection during ischemia. A cardiac-specific transgenic mouse overexpressing H11 kinase (2- to 7-fold protein increase) has been generated, and is characterized by cardiac hypertrophy with preserved function and protection against irreversible damage during ischemia/reperfusion. In this study, we tested whether H11 kinase also participates in the metabolic adaptation to cardiac hypertrophy and ischemia.


RESULTS
A yeast two-hybrid screen using H11 kinase as a bait in a human heart library revealed a potential interaction with phosphoglucomutase (PGM), the enzyme converting glucose 6-phosphate into glucose 1-phosphate. Interaction between H11 kinase and PGM was confirmed by co-immunoprecipitation. To test the biochemical relevance of this interaction, PGM activity was measured in the heart from wild type and transgenic mice, showing a 20% increase of Vmax in the transgenic group, without change in KM. Glycogen content was increased proportionately to the expression of the transgene, reaching a 40% increase in high-expression transgenic mice (7-fold increase in H11 kinase protein) versus wild type (p < 0.01). Increased incorporation of glucose into glycogen was coupled to a 3-fold increase in the protein expression of the glucose transporter GLUT1 in plasma membrane of transgenic mice (p < 0.01).


CONCLUSIONS
H11 kinase promotes the synthesis of glycogen, an essential fuel for the stressed heart in both conditions of overload and ischemia. Therefore, H11 kinase represents an integrative sensor in the cardiac adaptation to stress by coordinating cell growth, survival and metabolism.
Wang
Li
L
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Street, MSB G-609, Newark, NJ 07103, USA.
Zajac
Anna
A
Hedhli
Nadia
N
Depre
Christophe
C
D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D051272:Glucose Transporter Type 1; D006003:Glycogen / Q000096:biosynthesis* / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D047468:Immunoprecipitation; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D017202:Myocardial Ischemia; D009206:Myocardium / Q000378:metabolism*; D010733:Phosphoglucomutase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D015427:Reperfusion Injury; D019076:Transgenes; D020798:Two-Hybrid System Techniques
D051272:Glucose Transporter Type 1; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009004:Monosaccharide Transport Proteins; D011506:Proteins; C495677:SLC2A1 protein, human; C495678:Slc2a1 protein, mouse; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases; D010733:Phosphoglucomutase