Li Wang1, Anna Zajac, Nadia Hedhli, Christophe Depre. 1. 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.
Abstract
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. METHODS AND 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). CONCLUSION: 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.
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 transgenicmouse 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. METHODS AND 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). CONCLUSION: 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.
Authors: Christophe Depre; Song-Jung Kim; Anna S John; Yanhong Huang; Ornella E Rimoldi; John R Pepper; Gilles D Dreyfus; Vinciane Gaussin; Dudley J Pennell; Dorothy E Vatner; Paolo G Camici; Stephen F Vatner Journal: Circ Res Date: 2004-07-08 Impact factor: 17.367