The sodium-glucose co-transporter-2 inhibitor ertugliflozin modifies the signature of cardiac substrate metabolism and reduces cardiac mTOR signalling, endoplasmic reticulum stress and apoptosis.

Abstract

AIM:

To investigate cardiac signalling pathways connecting substrate utilization with left ventricular remodelling in a murine pressure overload model.

METHODS:

Cardiac hypertrophy was induced by transverse aortic constriction surgery in 20-week-old C57BL/6J mice treated with or without the sodium-glucose co-transporter 2 (SGLT2) inhibitor ertugliflozin (225 mg kg-1 chow diet) for 10 weeks.

RESULTS:

Ertugliflozin improved left ventricular function and reduced myocardial fibrosis. This occurred simultaneously with a fasting-like response characterized by improved glucose tolerance and increased ketone body concentrations. While cardiac insulin signalling was reduced in response to SGLT2 inhibition, AMP-activated protein kinase (AMPK) signalling was increased with induction of the fatty acid transporter cluster of differentiation 36 and phosphorylation of acetyl-CoA carboxylase (ACC). Further, enzymes responsible for ketone body catabolism (β-hydroxybutyrate dehydrogenase, succinyl-CoA:3-oxoacid-CoA transferase and acetyl-CoA acetyltransferase 1) were induced by SGLT2 inhibition. Ertugliflozin led to more cardiac abundance of fatty acids, tricarboxylic acid cycle metabolites and ATP. Downstream mechanistic target of rapamycin (mTOR) pathway, relevant for protein synthesis, cardiac hypertrophy and adverse cardiac remodelling, was reduced by SGLT2 inhibition, with alleviation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) providing a potential mechanism for abundant reduced left ventricular apoptosis and fibrosis.

CONCLUSION:

SGLT2 inhibition reduced left ventricular fibrosis in a murine model of cardiac hypertrophy. Mechanistically, this was associated with reduced cardiac insulin and increased AMPK signalling as a potential mechanism for less cardiac mTOR activation with alleviation of downstream ER stress, UPR and apoptosis.

• Authors: Julia Moellmann, Pascal A Mann, Ben A Kappel, Florian Kahles, Barbara M Klinkhammer, Peter Boor, Rafael Kramann, Bart Ghesquiere, Corinna Lebherz, Nikolaus Marx, Michael Lehrke
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 24 Issue 11 Pg. 2263-2272 (11 2022) ISSN: 1463-1326 [Electronic] England
• PMID: 35801343 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Fatty Acids
• Insulins
• Keto Acids
• Ketones
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• ertugliflozin
• Adenosine Triphosphate
• Sodium
• Hydroxybutyrate Dehydrogenase
• Acetyl-CoA C-Acetyltransferase
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinases
• Coenzyme A-Transferases
• Acetyl-CoA Carboxylase
• Glucose
• Sirolimus

Topics

• AMP-Activated Protein Kinases (metabolism)
• Acetyl-CoA C-Acetyltransferase (metabolism)
• Acetyl-CoA Carboxylase (metabolism)
• Adenosine Triphosphate (metabolism)
• Animals
• Apoptosis
• Bridged Bicyclo Compounds, Heterocyclic
• Cardiomegaly (metabolism, pathology)
• Coenzyme A-Transferases (metabolism)
• Endoplasmic Reticulum Stress
• Fatty Acids (metabolism)
• Fibrosis
• Glucose (metabolism)
• Hydroxybutyrate Dehydrogenase (metabolism)
• Insulins
• Keto Acids (metabolism)
• Ketones (metabolism)
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac (metabolism)
• Sirolimus (metabolism)
• Sodium (metabolism)
• Sodium-Glucose Transporter 2 (metabolism)
• Sodium-Glucose Transporter 2 Inhibitors (pharmacology, therapeutic use)
• TOR Serine-Threonine Kinases (metabolism)