Mark Luedde1, Matthias Lutz1, Natalie Carter1, Justyna Sosna2, Christoph Jacoby3, Mihael Vucur4, Jérémie Gautheron4, Christoph Roderburg4, Nadine Borg3, Florian Reisinger5, Hans-Joerg Hippe1, Andreas Linkermann6, Monika J Wolf7, Stefan Rose-John8, Renate Lüllmann-Rauch9, Dieter Adam2, Ulrich Flögel3, Mathias Heikenwalder6, Tom Luedde4, Norbert Frey10. 1. Department of Internal Medicine III: Cardiology and Angiology, University of Kiel, Arnold-Heller-Straße 3, Haus 6, 24105 Kiel, Germany. 2. Institute of Immunology, University of Kiel, Kiel, Germany. 3. Department of Molecular Cardiology, University of Duesseldorf, Duesseldorf, Germany. 4. Department of Internal Medicine III, University Hospital, Aachen, Germany. 5. Institute of Virology, Technical University of Munich, Munich, Germany. 6. Department of Nephrology, University of Kiel, Kiel, Germany. 7. Institute of Physiology, University of Zurich and Zurich Center for Integrative Human Physiology, Zurich, Switzerland. 8. Department of Biochemistry, University of Kiel, Kiel, Germany. 9. Department of Anatomy, University of Kiel, Kiel, Germany. 10. Department of Internal Medicine III: Cardiology and Angiology, University of Kiel, Arnold-Heller-Straße 3, Haus 6, 24105 Kiel, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany norbert.frey@uksh.de freynorbert@hotmail.com.
Abstract
AIMS: Programmed necrosis (necroptosis) represents a newly identified mechanism of cell death combining features of both apoptosis and necrosis. Like apoptosis, necroptosis is tightly regulated by distinct signalling pathways. A key regulatory role in programmed necrosis has been attributed to interactions of the receptor-interacting protein kinases, RIP1 and RIP3. However, the specific functional role of RIP3-dependent signalling and necroptosis in the heart is unknown. The aims of this study were thus to assess the significance of necroptosis and RIP3 in the context of myocardial ischaemia. METHODS AND RESULTS: Immunoblots revealed strong expression of RIP3 in murine hearts, indicating potential functional significance of this protein in the myocardium. Consistent with a role in promoting necroptosis, adenoviral overexpression of RIP3 in neonatal rat cardiomyocytes and stimulation with TNF-α induced the formation of a complex of RIP1 and RIP3. Moreover, RIP3 overexpression was sufficient to induce necroptosis of cardiomyocytes. In vivo, cardiac expression of RIP3 was up-regulated upon myocardial infarction (MI). Conversely, mice deficient for RIP3 (RIP3(-/-)) showed a significantly better ejection fraction (45 ± 3.6 vs. 32 ± 4.4%, P < 0.05) and less hypertrophy in magnetic resonance imaging studies 30 days after experimental infarction due to left anterior descending coronary artery ligation. This was accompanied by a diminished inflammatory response of infarcted hearts and decreased generation of reactive oxygen species. CONCLUSION: Here, we show that RIP3-dependent necroptosis modulates post-ischaemic adverse remodelling in a mouse model of MI. This novel signalling pathway may thus be an attractive target for future therapies that aim to limit the adverse consequences of myocardial ischaemia. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Programmed necrosis (necroptosis) represents a newly identified mechanism of cell death combining features of both apoptosis and necrosis. Like apoptosis, necroptosis is tightly regulated by distinct signalling pathways. A key regulatory role in programmed necrosis has been attributed to interactions of the receptor-interacting protein kinases, RIP1 and RIP3. However, the specific functional role of RIP3-dependent signalling and necroptosis in the heart is unknown. The aims of this study were thus to assess the significance of necroptosis and RIP3 in the context of myocardial ischaemia. METHODS AND RESULTS: Immunoblots revealed strong expression of RIP3 in murine hearts, indicating potential functional significance of this protein in the myocardium. Consistent with a role in promoting necroptosis, adenoviral overexpression of RIP3 in neonatal rat cardiomyocytes and stimulation with TNF-α induced the formation of a complex of RIP1 and RIP3. Moreover, RIP3 overexpression was sufficient to induce necroptosis of cardiomyocytes. In vivo, cardiac expression of RIP3 was up-regulated upon myocardial infarction (MI). Conversely, mice deficient for RIP3 (RIP3(-/-)) showed a significantly better ejection fraction (45 ± 3.6 vs. 32 ± 4.4%, P < 0.05) and less hypertrophy in magnetic resonance imaging studies 30 days after experimental infarction due to left anterior descending coronary artery ligation. This was accompanied by a diminished inflammatory response of infarcted hearts and decreased generation of reactive oxygen species. CONCLUSION: Here, we show that RIP3-dependent necroptosis modulates post-ischaemic adverse remodelling in a mouse model of MI. This novel signalling pathway may thus be an attractive target for future therapies that aim to limit the adverse consequences of myocardial ischaemia. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Sarah Colijn; Siqi Gao; Kyle G Ingram; Matthew Menendez; Vijay Muthukumar; Robert Silasi-Mansat; Joanna J Chmielewska; Myron Hinsdale; Florea Lupu; Courtney T Griffin Journal: Cell Death Differ Date: 2019-06-24 Impact factor: 15.828
Authors: Alexia Belavgeni; Stefan R Bornstein; Anne von Mässenhausen; Wulf Tonnus; Julian Stumpf; Claudia Meyer; Evelyn Othmar; Markus Latk; Waldemar Kanczkowski; Matthias Kroiss; Constanze Hantel; Christian Hugo; Martin Fassnacht; Christian G Ziegler; Andrew V Schally; Nils P Krone; Andreas Linkermann Journal: Proc Natl Acad Sci U S A Date: 2019-10-14 Impact factor: 11.205
Authors: Dominic P Del Re; Dulguun Amgalan; Andreas Linkermann; Qinghang Liu; Richard N Kitsis Journal: Physiol Rev Date: 2019-10-01 Impact factor: 37.312
Authors: Wenjun Li; Guoshuai Feng; Jason M Gauthier; Inessa Lokshina; Ryuji Higashikubo; Sarah Evans; Xinping Liu; Adil Hassan; Satona Tanaka; Markus Cicka; Hsi-Min Hsiao; Daniel Ruiz-Perez; Andrea Bredemeyer; Richard W Gross; Douglas L Mann; Yulia Y Tyurina; Andrew E Gelman; Valerian E Kagan; Andreas Linkermann; Kory J Lavine; Daniel Kreisel Journal: J Clin Invest Date: 2019-02-26 Impact factor: 14.808
Authors: Kim H H Liss; Kyle S McCommis; Kari T Chambers; Terri A Pietka; George G Schweitzer; Sara L Park; Ilke Nalbantoglu; Carla J Weinheimer; Angela M Hall; Brian N Finck Journal: Liver Transpl Date: 2018-07 Impact factor: 5.799