https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Heidelberg Molekulare Kardiologie und Epigenetik Heidelberg, Deutschland; 2Universitätsklinikum Heidelberg Institut für experimentelle Kardiologie Heidelberg, Deutschland; 3Department of Chronic Inflammation and cancer German Cancer Research Center Heidelberg,, Deutschland
Background. Diabetes Mellitus (DM) is a risk factor for incident heart failure. Our previous finding showed that histone deacetylase 4 (HDAC4) protects from diabetic cardiomyopathy in mice, however the molecular mechanism of the events remained poorly understood. In this study we investigate the role of nuclear receptor Nr4a1 as a HDAC4-target gene in an experimental model of diabetes induced by STZ.
Results. Here we unraveled the prominent role of Nr4a1, a key transcription factor of glucose and fatty acid metabolism, in cardiac systolic function in diabetes. We generated an inducible cardiomyocyte-specific HDAC4 knock-out (HDAC4-cKO), Nr4a1 knock-out (Nr4a1-cKO), and HDAC4/Nr4a1 double knock-out (DKO) mice. Mice were subjected to diabetes mellitus by streptozotocin injections (type 1 diabetes) for 10 weeks. HDAC4 cKO mice developed mild systolic dysfunction as expected. Strikingly, mice lacking HDAC4/Nr4a1 (DKO) exhibited rescue in systolic dysfunction. Transcriptomic analysis of isolated nuclear cardiomyocytes from left ventricular tissues revealed drastic up-regulation of Nr4a1 in HDAC4 cKO mice which was correlated with dysregulation of genes involved in metabolic remodeling specifically glucose and fatty acid metabolism. Immunohisto-staining of myocardial tissues revealed drastic downregulation of fatty acid transporter FAT/CD36 and upregulation of glucose transporter Glut4 in HDAC4-cKO mice which was consistent with the transcriptome data. However, the metabolic signature in HDAC4/Nr4a1 (DKO) mice remains similar to the control mice.
Conclusion. Taken together, these findings implicate HDAC4-Nr4a1 as a regulatory axis of pathological cardiac metabolic reprogramming in diabetes. A better understanding of this process may lead to new therapeutic strategies for treating diabetic cardiomyopathy.