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Effects of canagliflozin on human myocardial redox signalling: Clinical implications

Lookup NU author(s): Dr Chris Kotanidis



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( Aims: Recent clinical trials indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain unknown. We explored the direct effects of canagliflozin, an SGLT2 inhibitor with mild SGLT1 inhibitory effects, on myocardial redox signalling in humans. Methods and results: Study 1 included 364 patients undergoing cardiac surgery. Right atrial appendage biopsies were harvested to quantify superoxide (O2∙-) sources and the expression of inflammation, fibrosis, and myocardial stretch genes. In Study 2, atrial tissue from 51 patients was used ex vivo to study the direct effects of canagliflozin on NADPH oxidase activity and nitric oxide synthase (NOS) uncoupling. Differentiated H9C2 and primary human cardiomyocytes (hCM) were used to further characterize the underlying mechanisms (Study 3). SGLT1 was abundantly expressed in human atrial tissue and hCM, contrary to SGLT2. Myocardial SGLT1 expression was positively associated with O2∙- production and pro-fibrotic, pro-inflammatory, and wall stretch gene expression. Canagliflozin reduced NADPH oxidase activity via AMP kinase (AMPK)/Rac1signalling and improved NOS coupling via increased tetrahydrobiopterin bioavailability ex vivo and in vitro. These were attenuated by knocking down SGLT1 in hCM. Canagliflozin had striking ex vivo transcriptomic effects on myocardial redox signalling, suppressing apoptotic and inflammatory pathways in hCM. Conclusions We demonstrate for the first time that canagliflozin suppresses myocardial NADPH oxidase activity and improves NOS coupling via SGLT1/AMPK/Rac1 signalling, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings reveal a novel mechanism contributing to the beneficial cardiac effects of canagliflozin.

Publication metadata

Author(s): Kondo H, Akoumianakis I, Badi I, Akawi N, Kotanidis CP, Polkinghorne M, Stadiotti I, Sommariva E, Antonopoulos AS, Carena MC, Oikonomou EK, Reus EM, Sayeed R, Krasopoulos G, Srivastava V, Farid S, Chuaiphichai S, Shirodaria C, Channon KM, Casadei B, Antoniades C

Publication type: Article

Publication status: Published

Journal: European Heart Journal

Year: 2021

Volume: 42

Issue: 48

Pages: 4947-4960

Print publication date: 21/12/2021

Online publication date: 19/07/2021

Acceptance date: 18/06/2021

Date deposited: 21/12/2022

ISSN (print): 0195-668X

ISSN (electronic): 1522-9645

Publisher: Oxford University Press


DOI: 10.1093/eurheartj/ehab420

PubMed id: 34293101


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Funder referenceFunder name
Japanese Heart Rhythm Society-European Heart Rhythm Association
National Institute for Health Research Oxford Biomedical Research Centre