Loss of PKC-delta alters cardiac metabolism.
PKC-delta is believed to play an essential role in cardiomyocyte growth. In the present study, we investigated the effect of PKC-delta on cardiac metabolism using PKC-delta knockout mice generated in our laboratories. Proteomic analysis of heart protein extracts revealed profound changes in enzymes related to energy metabolism: certain isoforms of glycolytic enzymes, e.g., lactate dehydrogenase and pyruvate kinase, were absent or decreased, whereas several enzymes involved in lipid metabolism, e.g., phosphorylated isoforms of acyl-CoA dehydrogenases, showed a marked increase in PKC-delta(-/-) hearts. Moreover, PKC-delta deficiency was associated with changes in antioxidants, namely, 1-Cys peroxiredoxin and selenium-binding protein 1, and posttranslational modifications of chaperones involved in cytoskeleton regulation, such as heat shock protein (HSP)20, HSP27, and the zeta-subunit of the cytosolic chaperone containing the T-complex polypeptide 1. High-resolution NMR analysis of cardiac metabolites confirmed a significant decrease in the ratio of glycolytic end products (alanine + lactate) to end products of lipid metabolism (acetate) in PKC-delta(-/-) hearts. Taken together, our data demonstrate that loss of PKC-delta causes a shift from glucose to lipid metabolism in murine hearts, and we provide a detailed description of the enzymatic changes on a proteomic level. The consequences of these metabolic alterations on sensitivity to myocardial ischemia are further explored in the accompanyingpaper (20).
Department of Cardiac and Vascular Sciences, St George's Hospital Medical School, London SW17 0RE, UK.
Manuel
M
Mayr
Yuen-Li
YL
Chung
Ursula
U
Mayr
Emma
E
McGregor
Helen
H
Troy
Gottfried
G
Baier
Michael
M
Leitges
Michael J
MJ
Dunn
John R
JR
Griffiths
Qingbo
Q
Xu
D000818:Animals; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010544:Peroxidases / Q000378:metabolism; D054464:Peroxiredoxins; D011493:Protein Kinase C / Q000172:deficiency / Q000502:physiology*; D051745:Protein Kinase C-delta; D020543:Proteome / Q000378:metabolism
D018832:Molecular Chaperones; D020543:Proteome; D010544:Peroxidases; D054464:Peroxiredoxins; C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta