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Loss of PKC- alters cardiac metabolism

¹Department of Cardiac and Vascular Sciences and ²Department of Basic Medical Sciences, St. George's Hospital Medical School, London SW17 0RE, United Kingdom; ³Institute of Medical Biology and Human Genetics, University of Innsbruck, Innsbruck 6020, Austria; ⁴Max-Planck-Institute for Experimental Endocrinology, Hannover 30625, Germany; and ⁵Proteome Sciences and ⁶Institute of Psychiatry, King's College, London SE5 8AF, United Kingdom

Submitted 11 September 2003 ; accepted in final form 15 January 2004

PKC- is believed to play an essential role in cardiomyocyte growth. In the present study, we investigated the effect of PKC- on cardiac metabolism using PKC- 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-^–/– hearts. Moreover, PKC- 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 -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-^–/– hearts. Taken together, our data demonstrate that loss of PKC- 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).

protein kinase C; proteomics; nuclear magnetic resonance; mouse model; metabolomics

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