Cardiac function is modulated by the sympathetic nervous system via catecholamines released from cardiac sympathetic nerve endings and adrenal chromaffin cells. The co-transmitter Neuropeptide Y (NPY) is co-released with catecholamines and also modulates cardiac function. NPY has previously been reported as an independent predictor of mortality in heart failure patients. In experimental models, NPY induces cardiac hypertrophy and elevates cardiomyocyte intracellular Ca 2+ concentrations and Ca 2+ -dependent signalling. However, not much is known yet about the upstream regulation of NPY in the context of cardiac function modulation. Interestingly, a robust upregulation of NPY gene expression has been reported in macrophages lacking the nuclear receptor Nur77. We have shown that Nur77 deficiency in mice leads to alterations in cardiomyocyte Ca 2+ homeostasis and adverse cardiac remodelling in response to isoproterenol. As these effects may be explained by enhanced NPY action in Nur77-deficient (Nur77-KO) mice, we hypothesized that Nur77 is a regulator of NPY. We now show that Nur77 down-regulates NPY expression in and secretion from sympathetic cells in vitro . Furthermore, NPY levels are significantly higher in blood plasma and hearts from Nur77-KO compared to wildtype mice. Antagonism of NPY receptor 1 (NPY1R) attenuates cardiac hypertrophy and elevated cardiomyocyte Ca 2+ responses caused by Nur77 deficiency. Interestingly, cardiomyocyte-specific Nur77-deficient mice also exhibit elevated cardiomyocyte Ca 2+ levels, which is partially reduced by NPY1R antagonism, even though plasma and cardiac NPY levels are similar to control mice. In conclusion, the transcription factor Nur77 regulates cardiac function both via systemic mechanisms and in cardiomyocytes intrinsically, via NPY/NPY1R modulation. These results imply a novel role for Nur77 as a potential modifier gene in heart failure.