CaMKII regulates cardiac metabolic substrate switching during heart failure

Ali Reza Saadatmand (Heidelberg)1, M. Pepin (Heidelberg)2, J. Hartmann (Heidelberg)2, Q. Sun (Heidelberg)2, U. Haberkorn (Heidelberg)3, L. Schlicker (Heidelberg)4, J. Tyedmers (Heidelberg)2, A. Schulze (Heidelberg)4, J. Backs (Heidelberg)5

1Universitätsklinikum Heidelberg Molekulare Kardiologie und Epigenetik Heidelberg, Deutschland; 2Heidelberg University Institute of Experimental Cardiology Heidelberg, Deutschland; 3University Hospital Heidelberg Department of Nuclear medicine Heidelberg, Deutschland; 4German Cancer Research Center Division of Tumor Metabolism and Microenvironment Heidelberg, Deutschland; 5Universitätsklinikum Heidelberg Innere Medizin VIII, Institut für Experimentelle Kardiologie Heidelberg, Deutschland


Background. Heart failure (HF) is associated with metabolic remodeling of the myocardium from preferential fatty acid oxidation towards glucose utilization. This metabolic reprogramming leads to an enhanced flux of glucose byproducts that trigger protein O-GlcNAcylation of calcium handling proteins to cause systolic cardiac dysfunction.

Results. In this study we investigate the role of Ca2+/calmodulin-dependent protein kinase II (CaMKII), a key regulator in pathological cardiac remodeling, for metabolic reprogramming in experimental cardiac dysfunction. Dynamic positron emission tomography (PET) with the glucose analogue 2-deoxy-2-[18F] fluoro-D-glucose (FDG) revealed that wild type (WT) but not mice lacking CaMKIIδ and CaMKIIγ (double knockout; DKO) exhibited 6-fold higher myocardial glucose uptake following pressure overload that preceded onset of left ventricular hypertrophy (LVH) and systolic dysfunction (n=6). Conversely, cardiac lipid staining showed that lipid reservoir in CaMKII-DKO mice were markedly higher as compared to WT littermates under pathological pressure overload. Transcriptomic analysis of left ventricular tissue revealed robust up-regulation of Nr4a1, a key transcription factor of glucose metabolism, which was accompanied by down-regulation of genes encoding intermediates of fatty acid (FA) uptake and utilization in WT mice following pressure overload as compared to DKO. Pointing to Nr4a1 as one of the top CaMKII-dependent genes, we generated for the first time cardiac-specific Nr4a1 knockout (Nr4a1-cKO) mice, which largely phenocopied the metabolic phenotype of CaMKII-DKO. Steady-state analysis of metabolomics profiling from cardiac samples revealed drastic depletion of storage lipids triacylglycerols (TAGs) in WT mice as compared to Nr4a1-KO littermates under pathological pressure overload. Adenoviral overexpression of Nr4a1 in human iPSC-derived cardiomyocytes (iPSC-CM) suppresses expression of genes involved in FA uptake and utilization. Mechanistically, we found that Nr4a1 directly binds to the promoter of FA transporter FATP1 (Slc27a1) resulting in suppression of its transcription.

Conclusion. Taken together, these findings implicate CaMKII-Nr4a1 as a regulatory axis of pathological cardiac metabolic reprogramming. A better understanding of this process may lead to new therapeutic strategies for treating cardiomyopathies.

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