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.
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.
Authors: Stephen D Wiviott; Itamar Raz; Marc P Bonaca; Ofri Mosenzon; Eri T Kato; Avivit Cahn; Michael G Silverman; Thomas A Zelniker; Julia F Kuder; Sabina A Murphy; Deepak L Bhatt; Lawrence A Leiter; Darren K McGuire; John P H Wilding; Christian T Ruff; Ingrid A M Gause-Nilsson; Martin Fredriksson; Peter A Johansson; Anna-Maria Langkilde; Marc S Sabatine Journal: N Engl J Med Date: 2018-11-10 Impact factor: 91.245
Authors: Kenneth W Mahaffey; Bruce Neal; Vlado Perkovic; Dick de Zeeuw; Greg Fulcher; Ngozi Erondu; Wayne Shaw; Elisa Fabbrini; Tao Sun; Qiang Li; Mehul Desai; David R Matthews Journal: Circulation Date: 2017-11-13 Impact factor: 29.690
Authors: Nikole J Byrne; Nirmal Parajuli; Jody L Levasseur; Jamie Boisvenue; Donna L Beker; Grant Masson; Paul W M Fedak; Subodh Verma; Jason R B Dyck Journal: JACC Basic Transl Sci Date: 2017-08-04
Authors: Detmar Kolijn; Steffen Pabel; Yanna Tian; Mária Lódi; Melissa Herwig; Albino Carrizzo; Saltanat Zhazykbayeva; Árpád Kovács; Gábor Á Fülöp; Inês Falcão-Pires; Peter H Reusch; Sophie Van Linthout; Zoltán Papp; Loek van Heerebeek; Carmine Vecchione; Lars S Maier; Michele Ciccarelli; Carsten Tschöpe; Andreas Mügge; Zsolt Bagi; Samuel Sossalla; Nazha Hamdani Journal: Cardiovasc Res Date: 2021-01-21 Impact factor: 10.787
Authors: Katarina Andelova; Barbara Szeiffova Bacova; Matus Sykora; Peter Hlivak; Miroslav Barancik; Narcis Tribulova Journal: Int J Mol Sci Date: 2022-01-26 Impact factor: 5.923