In:
Diabetes, Obesity and Metabolism, Wiley, Vol. 24, No. 11 ( 2022-11), p. 2263-2272
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1462-8902
,
1463-1326
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
2004918-3
