Effects of canagliflozin on human myocardial redox signalling: clinical implications
| Autor: | Vivek Srivastava, Ioannis Akoumianakis, Keith M. Channon, George Krasopoulos, Elsa Mauricio Reus, Alexios S. Antonopoulos, Rana Sayeed, Murray Polkinghorne, Surawee Chuaiphichai, Nadia Akawi, Shakil Farid, Elena Sommariva, H Kondo, Christos P Kotanidis, Barbara Casadei, Evangelos Oikonomou, Cheerag Shirodaria, Ilaria Stadiotti, Maria Cristina Carena, Ileana Badi, Charalambos Antoniades |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Myocardial redox state AMPK NADPH oxidase activity Inflammation 030204 cardiovascular system & hematology Pharmacology SGLT1 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Fibrosis Translational Research medicine Humans Myocytes Cardiac AcademicSubjects/MED00200 Canagliflozin Sodium-Glucose Transporter 2 Inhibitors Heart Failure and Cardiomyopathies biology Superoxide business.industry Myocardium SGLT2 inhibitor Tetrahydrobiopterin medicine.disease Nitric oxide synthase Oxidative Stress 030104 developmental biology chemistry biology.protein cardiovascular system medicine.symptom NOS coupling Cardiology and Cardiovascular Medicine business Oxidation-Reduction Ex vivo medicine.drug |
| Zdroj: | European Heart Journal |
| ISSN: | 1522-9645 0195-668X |
| Popis: | 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. Graphical Abstract Proposed mechanism of canagliflozin-induced improvement of myocardial redox state. Canagliflozin increases intracellular AMP/ATP ratio through inhibition of SGLT1, which can activate AMPK/NOS signalling and increase NO that suppresses pro-inflammatory signalling. AMPK activation also inhibits activation of Rac1 and membrane translocation of Rac1 and p47phox, which decrease NADPH oxidase activity and superoxide (O2.−) production, attenuates inflammatory and apoptotic pathways and increasing the bioavailability of tetrahydrobiopterin (BH4), a key factor for NOS coupling. |
| Databáze: | OpenAIRE |
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