Cardiac Microvascular Endothelial Enhancement of Cardiomyocyte Function Is Impaired by Inflammation and Restored by Empagliflozin.

•CMECs exert a direct positive effect on cardiomyocyte contraction and relaxation, which is mainly mediated by endothelial-derived NO.•Pro-inflammatory stimulation of CMECs by pre-incubation with TNF-α or interleukin-1β abrogates the positive regulatory function of these cells on cardiomyocyte contractile property.•Mechanistically, pro-inflammatory activation of CMECs leads to mitochondrial and cytoplasmic ROS accumulation that results in the scavenging of NO.•Empagliflozin directly restores the beneficial effect of CMECs on cardiomyocyte contraction and relaxation by reducing TNF-α-induced mitochondrial and cytoplasmic ROS accumulation, which leads to reinstatement of CMEC-derived NO delivery.