Fig. 2

SGLT2i and the Sodium-interactome of cardiac cells. Stress conditions will activate the sodium/hydrogen exchanger (NHE) and/or sodium channel (Nav1.5) and/or induce expression of SGLT2 in the plasma membrane facilitating increases in cytosolic sodium ([Na⁺]_I. Increases in ([Na⁺]_I can result in increased calcium ([Ca²⁺]_I through impairment of NCX. ([Na⁺]_I will transfer into mitochondria through the sodium/calcium exchanger (NCLX) in the mitochondrial membrane, increasing mitochondrial Na⁺ and decreasing mitochondrial Ca²⁺. Decreased mitochondrial Ca²⁺ shifts metabolism away from fatty acid oxidation (FAO) towards glucose oxidation (GO) and facilitates ROS production through diminished anti-oxidant activity of ROS detoxifying enzyme systems. Increased mitochondrial Na⁺ can increase mitochondrial ROS through decreases in membrane fluidity. Increased cytosolic Ca²⁺ stimulates hypertrophy through calcineurin activation, cytosolic ROS production through activation of NADPH oxidase, and inflammation through activation of the Nlrp3 inflammasome. Oxidative stress and inflammation causes cardiac dysfunction and positively feed backs to the NHE and Nav1.5 by activating these channels