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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 (http://creativecommons.org/licenses/by-nc/4.0/). 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.
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
URL: https://doi.org/10.1093/eurheartj/ehab420
DOI: 10.1093/eurheartj/ehab420
PubMed id: 34293101
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