title: RIP3, a kinase promoting necroptotic cell death, mediates adverse remodelling after myocardial infarction.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine III: Cardiology and Angiology, University of Kiel, Arnold-Heller-Straße 3, Haus 6, 24105 Kiel, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Luedde
authors.affiliation: Department of Internal Medicine III: Cardiology and Angiology, University of Kiel, Arnold-Heller-Straße 3, Haus 6, 24105 Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lutz
authors.affiliation: Department of Internal Medicine III: Cardiology and Angiology, University of Kiel, Arnold-Heller-Straße 3, Haus 6, 24105 Kiel, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Carter
authors.affiliation: Institute of Immunology, University of Kiel, Kiel, Germany.
authors.forename: Justyna
authors.initials: J
authors.lastname: Sosna
authors.affiliation: Department of Molecular Cardiology, University of Duesseldorf, Duesseldorf, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Jacoby
authors.affiliation: Department of Internal Medicine III, University Hospital, Aachen, Germany.
authors.forename: Mihael
authors.initials: M
authors.lastname: Vucur
authors.affiliation: Department of Internal Medicine III, University Hospital, Aachen, Germany.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Gautheron
authors.affiliation: Department of Internal Medicine III, University Hospital, Aachen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Roderburg
authors.affiliation: Department of Molecular Cardiology, University of Duesseldorf, Duesseldorf, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Borg
authors.affiliation: Institute of Virology, Technical University of Munich, Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Reisinger
authors.affiliation: Department of Internal Medicine III: Cardiology and Angiology, University of Kiel, Arnold-Heller-Straße 3, Haus 6, 24105 Kiel, Germany.
authors.forename: Hans-Joerg
authors.initials: HJ
authors.lastname: Hippe
authors.affiliation: Department of Nephrology, University of Kiel, Kiel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Linkermann
authors.affiliation: Institute of Physiology, University of Zurich and Zurich Center for Integrative Human Physiology, Zurich, Switzerland.
authors.forename: Monika J
authors.initials: MJ
authors.lastname: Wolf
authors.affiliation: Department of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Department of Anatomy, University of Kiel, Kiel, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.affiliation: Institute of Immunology, University of Kiel, Kiel, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Adam
authors.affiliation: Department of Molecular Cardiology, University of Duesseldorf, Duesseldorf, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Flögel
authors.affiliation: Department of Nephrology, University of Kiel, Kiel, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Department of Internal Medicine III, University Hospital, Aachen, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
authors.affiliation: 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.
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; C582791:Ripk3 protein, rat
keywords: Inflammation; Myocardial infarction; Programmed necrosis; Receptor interacting protein 3; Remodelling