SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy

Abstract

Background: Elevated myocardial intracellular sodium ([Na⁺]_i) was shown to decrease mitochondrial calcium ([Ca²⁺]_MITO) via mitochondrial sodium/calcium exchanger (NCX_MITO), resulting in decreased mitochondrial ATP synthesis. The sodium-glucose co-transporter 2 inhibitor (SGLT2i) ertugliflozin (ERTU) improved energetic deficit and contractile dysfunction in a mouse model of high fat, high sucrose (HFHS) diet-induced diabetic cardiomyopathy (DCMP). As SGLT2is were shown to lower [Na⁺]_i in isolated cardiomyocytes, we hypothesized that energetic improvement in DCMP is at least partially mediated by a decrease in abnormally elevated myocardial [Na⁺]_i.

Methods: Forty-two eight-week-old male C57BL/6J mice were fed a control or HFHS diet for six months. In the last month, a subgroup of HFHS-fed mice was treated with ERTU. At the end of the study, left ventricular contractile function and energetics were measured simultaneously in isolated beating hearts by ³¹P NMR (Nuclear Magnetic Resonance) spectroscopy. A subset of untreated HFHS hearts was perfused with vehicle vs. CGP 37157, an NCX_MITO inhibitor. Myocardial [Na⁺]_i was measured by ²³Na NMR spectroscopy.

Results: HFHS hearts showed diastolic dysfunction, decreased contractile reserve, and impaired energetics as reflected by decreased phosphocreatine (PCr) and PCr/ATP ratio. Myocardial [Na⁺]_i was elevated > 2-fold in HFHS (vs. control diet). ERTU reversed the impairments in HFHS hearts to levels similar to or better than control diet and decreased myocardial [Na⁺]_i to control levels. CGP 37157 normalized the PCr/ATP ratio in HFHS hearts.

Conclusions: Elevated myocardial [Na⁺]_i contributes to mitochondrial and contractile dysfunction in DCMP. Targeting myocardial [Na⁺]_i and/or NCX_MITO may be an effective strategy in DCMP and other forms of heart disease associated with elevated myocardial [Na⁺]_i.

Keywords: Cardiac energetics; Contractile function; Diabetic cardiomyopathy; Ertugliflozin; Myocardial intracellular sodium; Sodium-glucose co-transporter 2 (SGLT2) inhibitor.