Effects of Sodium-Glucose Linked Transporter 2 Inhibition With Ertugliflozin on Mitochondrial Function, Energetics, and Metabolic Gene Expression in the Presence and Absence of Diabetes Mellitus in Mice

J Am Heart Assoc. 2021 Jul 6;10(13):e019995. doi: 10.1161/JAHA.120.019995. Epub 2021 Jun 25.

Abstract

Background Inhibitors of the sodium-glucose linked transporter 2 improve cardiovascular outcomes in patients with or without type 2 diabetes mellitus, but the effects on cardiac energetics and mitochondrial function are unknown. We assessed the effects of sodium-glucose linked transporter 2 inhibition on mitochondrial function, high-energy phosphates, and genes encoding mitochondrial proteins in hearts of mice with and without diet-induced diabetic cardiomyopathy. Methods and Results Mice fed a control diet or a high-fat, high-sucrose diet received ertugliflozin mixed with the diet (0.5 mg/g of diet) for 4 months. Isolated mitochondria were assessed for functional capacity. High-energy phosphates were assessed by 31P nuclear magnetic resonance spectroscopy concurrently with contractile performance in isolated beating hearts. The high-fat, high-sucrose diet caused myocardial hypertrophy, diastolic dysfunction, mitochondrial dysfunction, and impaired energetic response, all of which were prevented by ertugliflozin. With both diets, ertugliflozin caused supernormalization of contractile reserve, as measured by rate×pressure product at high work demand. Likewise, the myocardial gene sets most enriched by ertugliflozin were for oxidative phosphorylation and fatty acid metabolism, both of which were enriched independent of diet. Conclusions Ertugliflozin not only prevented high-fat, high-sucrose-induced pathological cardiac remodeling, but improved contractile reserve and induced the expression of oxidative phosphorylation and fatty acid metabolism gene sets independent of diabetic status. These effects of sodium-glucose linked transporter 2 inhibition on cardiac energetics and metabolism may contribute to improved structure and function in cardiac diseases associated with mitochondrial dysfunction, such as heart failure.

Keywords: cardiac metabolism; diabetic cardiomyopathy; energetics; mitochondria; sodium‐glucose linked transporter 2 inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetic Cardiomyopathies / etiology
  • Diabetic Cardiomyopathies / metabolism
  • Diabetic Cardiomyopathies / physiopathology
  • Diabetic Cardiomyopathies / prevention & control*
  • Diet, High-Fat
  • Dietary Sucrose
  • Energy Metabolism / drug effects*
  • Energy Metabolism / genetics
  • Gene Expression Regulation
  • Hypertrophy, Left Ventricular / etiology
  • Hypertrophy, Left Ventricular / metabolism
  • Hypertrophy, Left Ventricular / physiopathology
  • Hypertrophy, Left Ventricular / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / genetics
  • Mitochondria, Heart / metabolism
  • Myocardial Contraction / drug effects
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Oxidative Stress / drug effects
  • Sodium-Glucose Transporter 2 Inhibitors / pharmacology*
  • Ventricular Dysfunction, Left / etiology
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Dysfunction, Left / prevention & control*
  • Ventricular Function, Left / drug effects
  • Ventricular Remodeling / drug effects

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Dietary Sucrose
  • Sodium-Glucose Transporter 2 Inhibitors
  • ertugliflozin