Sean Kang1, Subodh Verma2, Ali Fatehi Hassanabad1, Guoqi Teng1, Darrell D Belke1, Jameson A Dundas1, David G Guzzardi1, Daniyil A Svystonyuk1, Simranjit S Pattar1, Daniel S J Park1, Jeannine D Turnbull1, Henry J Duff1, Lee Anne Tibbles3, Ryan H Cunnington3, Jason R B Dyck4, Paul W M Fedak5. 1. Section of Cardiac Surgery, Department of Cardiac Sciences, Cumming School of Medicine, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada. 2. Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. 3. Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 4. Cardiovascular Research Centre, Mazankowski Alberta Health Institute, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. 5. Section of Cardiac Surgery, Department of Cardiac Sciences, Cumming School of Medicine, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada. Electronic address: paul.fedak@gmail.com.
Abstract
BACKGROUND: Empagliflozin, an SGLT2 inhibitor, has shown remarkable reductions in cardiovascular mortality and heart failure admissions (EMPA-REG OUTCOME). However, the mechanism underlying the heart failure protective effects of empagliflozin remains largely unknown. Cardiac fibroblasts play an integral role in the progression of structural cardiac remodelling and heart failure, in part, by regulating extracellular matrix (ECM) homeostasis. The objective of this study was to determine if empagliflozin has a direct effect on human cardiac myofibroblast-mediated ECM remodelling. METHODS: Cardiac fibroblasts were isolated via explant culture from human atrial tissue obtained at open heart surgery. Collagen gel contraction assay was used to assess myofibroblast activity. Cell morphology and cell-mediated ECM remodelling was examined with the use of confocal microscopy. Gene expression of profibrotic markers was assessed with the use of reverse-transcription quantitative polymerase chain reaction. RESULTS: Empagliflozin significantly attenuated transforming growth factor β1-induced fibroblast activation via collagen gel contraction after 72-hour exposure, with escalating concentrations (0.5 μmol/L, 1 μmol/L, and 5 μmol/L) resulting in greater attenuation. Morphologic assessment showed that myofibroblasts exposed to empagliflozin were smaller in size with shorter and fewer number of extensions, indicative of a more quiescent phenotype. Moreover, empagliflozin significantly attenuated cell-mediated ECM remodelling as measured by collagen fibre alignment index. Gene expression profiling revealed significant suppression of critical profibrotic markers by empagliflozin, including COL1A1, ACTA2, CTGF, FN1, and MMP-2. CONCLUSIONS: We provide novel data showing a direct effect of empagliflozin on human cardiac myofibroblast phenotype and function by attenuation of myofibroblast activity and cell-mediated collagen remodelling. These data provide critical insights into the profound effects of empagliflozin as noted in the EMPA-REG OUTCOME study.
BACKGROUND:Empagliflozin, an SGLT2 inhibitor, has shown remarkable reductions in cardiovascular mortality and heart failure admissions (EMPA-REG OUTCOME). However, the mechanism underlying the heart failure protective effects of empagliflozin remains largely unknown. Cardiac fibroblasts play an integral role in the progression of structural cardiac remodelling and heart failure, in part, by regulating extracellular matrix (ECM) homeostasis. The objective of this study was to determine if empagliflozin has a direct effect on human cardiac myofibroblast-mediated ECM remodelling. METHODS: Cardiac fibroblasts were isolated via explant culture from human atrial tissue obtained at open heart surgery. Collagen gel contraction assay was used to assess myofibroblast activity. Cell morphology and cell-mediated ECM remodelling was examined with the use of confocal microscopy. Gene expression of profibrotic markers was assessed with the use of reverse-transcription quantitative polymerase chain reaction. RESULTS:Empagliflozin significantly attenuated transforming growth factor β1-induced fibroblast activation via collagen gel contraction after 72-hour exposure, with escalating concentrations (0.5 μmol/L, 1 μmol/L, and 5 μmol/L) resulting in greater attenuation. Morphologic assessment showed that myofibroblasts exposed to empagliflozin were smaller in size with shorter and fewer number of extensions, indicative of a more quiescent phenotype. Moreover, empagliflozin significantly attenuated cell-mediated ECM remodelling as measured by collagen fibre alignment index. Gene expression profiling revealed significant suppression of critical profibrotic markers by empagliflozin, including COL1A1, ACTA2, CTGF, FN1, and MMP-2. CONCLUSIONS: We provide novel data showing a direct effect of empagliflozin on human cardiac myofibroblast phenotype and function by attenuation of myofibroblast activity and cell-mediated collagen remodelling. These data provide critical insights into the profound effects of empagliflozin as noted in the EMPA-REG OUTCOME study.
Authors: Yuling Yan; Bin Liu; Jun Du; Jing Wang; Xiaodong Jing; Yajie Liu; Songbai Deng; Jianlin Du; Qiang She Journal: ESC Heart Fail Date: 2021-03-21
Authors: Dimitrios A Vrachatis; Konstantinos A Papathanasiou; Konstantinos E Iliodromitis; Sotiria G Giotaki; Charalampos Kossyvakis; Konstantinos Raisakis; Andreas Kaoukis; Vaia Lambadiari; Dimitrios Avramides; Bernhard Reimers; Giulio G Stefanini; Michael Cleman; Georgios Giannopoulos; Alexandra Lansky; Spyridon G Deftereos Journal: Drugs Date: 2021-07-23 Impact factor: 9.546
Authors: David Bode; Lukas Semmler; Christian U Oeing; Alessio Alogna; Gabriele G Schiattarella; Burkert M Pieske; Frank R Heinzel; Felix Hohendanner Journal: Int J Mol Sci Date: 2021-05-31 Impact factor: 5.923