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Title: Cytoprotective activated protein C averts Nlrp3 inflammasome induced ischemia reperfusion injury via mTORC1 inhibition
Author(s): Nazir, Sumra
Referee(s): Dudeck, Anne
Chavakis, Triantafyllos
Granting Institution: Otto-von-Guericke-Universität Magdeburg
Issue Date: 2018
Type: Doctoral thesis
Exam Date: 2019
Language: English
Publisher: Otto-von-Guericke-Universität Magdeburg
URN: urn:nbn:de:gbv:ma9:1-1981185920-325014
Subjects: Protein C
Abstract: Cytoprotection by activated protein C (aPC) following ischemia-reperfusion injury (IRI) is associated with apoptosis inhibition. However, IRI is hallmarked by inflammation and hence conceptually cell-death forms disjunct from immunologically silent apoptosis are more likely to be relevant. As pyroptosis, cell death resulting from inflammasome activation, is typically observed in IRI we speculated that aPC ameliorates IRI by inhibiting inflammasome activation. Here we analyzed the impact of aPC on inflammasome activity in myocardial and renal IRI. aPC treatment reduced infarct size and Nlrp3 inflammasome activation in mice. Kinetic in vivo analyses revealed that inflammasome activation preceded myocardial injury and apoptosis. The constitutively active Nlrp3A350V mutant abolished aPC’s protective effect, demonstrating that Nlrp3 suppression is required for aPC-mediated protection from IRI. In vitro aPC inhibited inflammasome activation via PAR-1 and mTORC1 signaling. Inhibiting PAR-1 signaling abolished aPC’s ability to restrict inflammasome activity and myocardial infarction, while specifically inhibiting aPC’s anticoagulant properties did not impair aPC’s effect on inflammasome activation. Targeting biased PAR-1 signaling via parmodulin-2 restricted inflammasome activation and limited myocardial IRI. aPC’s renal tissue protective effect was likewise dependent on Nlrp3 inflammasome suppression. These studies reveal that aPC protects from IRI by restricting mTORC1 dependent inflammasome activation and that mimicking biased aPC-PAR1 signaling using parmodulins may be a feasible therapeutic approach to combat IRI.
Open Access: Open access publication
License: (CC BY-SA 4.0) Creative Commons Attribution ShareAlike 4.0(CC BY-SA 4.0) Creative Commons Attribution ShareAlike 4.0
Appears in Collections:Medizinische Fakultät

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