Empagliflozin inhibits Na⁺/H⁺ exchanger activity in human atrial cardiomyocytes

Abstract

Aims Recent clinical trials have proven gliflozins to be cardioprotective in diabetic and non-diabetic patients. However, the underlying mechanisms are incompletely understood. A potential inhibition of cardiac Na + /H + exchanger 1 (NHE1) has been suggested in animal models. We investigated the effect of empagliflozin on NHE1 activity in human atrial cardiomyocytes. Methods and results Expression of NHE1 was assessed in human atrial and ventricular tissue via western blotting. NHE activity was measured as the maximal slope of pH recovery after NH 4 + pulse in isolated carboxy-seminaphtarhodafluor 1 (SNARF1)-acetoxymethylester-loaded murine ventricular and human atrial cardiomyocytes. NHE1 is abundantly expressed in human atrial and ventricular tissue. Interestingly, compared with patients without heart failure (HF), atrial NHE1 expression was significantly increased in patients with HF with preserved ejection fraction and atrial fibrillation. The largest increase in atrial and ventricular NHE1 expression, however, was observed in patients with end-stage HF undergoing heart transplantation. Importantly, acute exposure to empagliflozin (1 μmol/L, 10 min) significantly inhibited NHE activity to a similar extent in human atrial myocytes and mouse ventricular myocytes. This inhibition was also achieved by incubation with the well-described selective NHE inhibitor cariporide (10 μmol/L, 10 min). Conclusions This is the first study systematically analysing NHE1 expression in human atrial and ventricular myocardium of HF patients. We show that empagliflozin inhibits NHE in human cardiomyocytes. The extent of NHE inhibition was comparable with cariporide and may potentially contribute to the improved outcome of patients in clinical trials.

Empagliflozin Decreases Lactate Generation in an NHE-1 Dependent Fashion and Increases α-Ketoglutarate Synthesis From Palmitate in Type II Diabetic Mouse Hearts

“…Secondly, we (5, 6) and others (9)(10)(11) found evidence that SGLT2i's may, at least partly, mediate their direct cellular effects through NHE-1 inhibition. A similar NHE-1 inhibition by empagliflozin was recently observed for human failing heart cardiomyocytes (12). SGLT2i inhibition of NHE results in intracellular ion changes of Na + and Ca 2+ (5,6) that may precipitate in changes in mitochondrial function (13) and can reprogram cardiac metabolism (14).…”

The Impact of Antidiabetic Therapies on Diastolic Dysfunction and Diabetic Cardiomyopathy

“…In follow-up studies from these same investigators, in-situ molecular modeling demonstrated that empagliflozin, dapagliflozin, and canagliflozin all favorably bind the NHE at the extracellular Na + -binding site, leading to an inhibition of NHE activity (Uthman et al, 2018). These findings have also recently been recapitulated in human atrial cardiac myocytes exposed to 1 µM empagliflozin, with the level of NHE inhibition being comparable to that observed with 10 µM cariporide (Trum et al, 2020). Taken together, the completed preclinical studies to date suggest that SGLT2 inhibitors positively influence multiple factors strongly associated with improvements in diastolic function in T2DM, and possibly through a combination of indirect on-target and direct off-target effects.…”

Cardioprotection by SGLT2 Inhibitors—Does It All Come Down to Na+?

“…It is still unclear, if the observed increase of NHE1 activity in heart failure is due to an increase in channel expression, posttranslational modification of the channel, or both. We have recently reported that NHE1 expression is markedly upregulated in ventricular tissue of patients with end-stage heart failure as compared to patients with left ventricular hypertrophy and normal systolic function [ 15 ]. Intriguingly, NHE1 expression has also been shown to be upregulated in the failing right ventricles of a rat model of pulmonary hypertension [ 62 ].…”

“…Therefore, many (pre-) clinical trials were performed to gain further mechanistic insights. Consequently, a myriad of potential mechanisms was proposed including direct cardiac effects such as inhibition of cardiac Na + /H + exchanger 1 (NHE1) [ 13 , 14 , 15 ], Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) [ 10 , 16 ], and late Na + current (late I Na ) [ 17 ]. Intriguingly, these proteins are centrally involved in cardiac Na + homeostasis, which is fundamentally disrupted in heart failure [ 18 , 19 , 20 ], making it an interesting target for heart failure treatment.…”