The off-target NHE1 inhibitory effect of SGLT2 inhibitors in cardiac remodeling

Abstract

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, approved for the treatment of diabetes mellitus, have gained attention for their cardioprotective effect. The exact mechanism by which SGLT-2 inhibitors exert their cardioprotective effect remains unclear. Recent studies have suggested that empagliflozin (EMPA), an SGLT inhibitor, exerts its car¬dioprotective effect by inhibiting the Na+/H+ exchanger (NHE); a group of membrane proteins that regulate intracel¬lular pH and cell volume. Increased activity and expression of NHE isoform 1 (NHE1), the predominant isoform ex¬pressed in the heart, leads to cardiac hypertrophy. Our research group investigates the indirect mechanisms by which SGLT inhibitors exert their cardioprotective effect and have demonstrated that angiotensin II (ANG)-induced hyper¬trophy of H9c2 cardiomyoblasts is accompanied with increased SGLT-1 and NHE1 protein expression; an effect which is reversed in the presence of EMPA. In addition, we demonstrated that dapagliflozin improved survival of transgenic mice expressing cardiac-specific NHE1.