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Diabetes mellitus (DM)-induced cardiac morbidities have been the leading cause of death among diabetic patients. Recently, sodium-glucose cotransporter-2 (SGLT-2) inhibitors including empagliflozin (EMPA), which have been approved for the treatment of DM, have gained attention for their cardioprotective effect. The mechanism by which SGLT-2 inhibitors exert their cardioprotective effect remains unclear. Recent studies have suggested that EMPA exerts its cardioprotective effect by inhibiting the Na + /H + exchanger (NHE), a group of membrane proteins that regulate intracellular pH and cell volume. Increased activity and expression of NHE isoform 1 (NHE1), the predominant isoform expressed in the heart, leads to cardiac hypertrophy. p90 ribosomal s6 kinase (p90 RSK) has been demonstrated to stimulate NHE1 activity. In our study, H9c2 cardiomyoblasts were treated with angiotensin II (ANG) to activate NHE1 and generate a hypertrophic model. We aimed to understand whether EMPA reverses the ANG-induced hypertrophic response and to elucidate the molecular pathway contributing to the cardioprotective effect of EMPA. Our study demonstrated that ANG-induced hypertrophy of H9c2 cardiomyoblasts is accompanied with increased SGLT-1 and NHE1 protein expression, an effect which is prevented in the presence of EMPA. EMPA reduces ANG-induced hypertrophy through the inhibition of SGLT-1 and NHE1 expression., (© 2022. The Author(s).)

Abnormality in glucose homeostasis due to hyperglycemia or insulin resistance is the hallmark of type 2 diabetes mellitus (T2DM). These metabolic abnormalities in T2DM lead to cellular dysfunction and the development of diabetic cardiomyopathy leading to heart failure. New antihyperglycemic agents including glucagon-like peptide-1 receptor agonists and the sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to attenuate endothelial dysfunction at the cellular level. In addition, they improved cardiovascular safety by exhibiting cardioprotective effects. The mechanism by which these drugs exert their cardioprotective effects is unknown, although recent studies have shown that cardiovascular homeostasis occurs through the interplay of the sodium-hydrogen exchangers (NHE), specifically NHE1 and NHE3, with SGLT2i. Another theoretical explanation for the cardioprotective effects of SGLT2i is through natriuresis by the kidney. This theory highlights the possible involvement of renal NHE transporters in the management of heart failure. This review outlines the possible mechanisms responsible for causing diabetic cardiomyopathy and discusses the interaction between NHE and SGLT2i in cardiovascular diseases.