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dc.contributor.authorBena, Stefania
dc.date.accessioned2015-07-15T14:53:49Z
dc.date.available2015-07-15T14:53:49Z
dc.date.issued2014-09-28
dc.identifier.citationBena, S. 2014. EXPRESSION AND FUNCTION OF THE FORMYL PEPTIDE RECEPTOR 2 IN EXPERIMENTAL MYOCARDIAL INFARCT. Queen Mary University of Londonen_US
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/7905
dc.descriptionThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the authoren_US
dc.description.abstractIn Acute Myocardial Infarction (AMI), inflammation is a prerequisite for healing but it can paradoxically extend tissue injury; hence it needs to be modulated. Here, we investigated the role of the pro resolving GPCR FPR2/ALX and its agonist Annexin A1 (AnxA1) in AMI using mice lacking of the Fpr2/3 genes and with an in-frame GFP gene ‘knocked-in’. We developed protocols aimed to determine GFP expression as an indication of Fpr2 gene activity. Also, the Left Anterior Descending Coronary Artery of male Fpr2/3 KO and littermate controls (WT) was occluded for 30min and re-opened for 90min. At the end tissue injury and inflammatory response were studied. A significant proportion of Fpr2/3 KO perished during the procedure. The rest survived up to 90 min and exhibited a larger infarct size, with higher troponin I and inflammation markers (KC, TNFα) than WT animals. At the end of reperfusion, Fpr2/3 KO displayed an unbalanced production of pro and anti-inflammatory lipids (higher PGE2, PGI2, LTB4 and attenuated PGA1, RvD2, LXA4) and a deregulated activation of the cardioprotective IL-6/JAK/STAT3 signalling. Administration of AnxA1 afforded cardioprotection (reduction of infarct size; Troponin I, Caspase3 activity and TNFα) in WT but not in Fpr2/3 KO. A parallel in vitro investigation on the functional FPR2/ALX domains required by AnxA1 and other agonists was also conducted. HEK-293 cells transfected with FPR1, FPR2/ALX and FPR1/FPR2 chimeric receptor were used and calcium flux, 4 pERK and gene modulation analysed. AnxA1 required the N-terminus and the II and III extracellular loops of FPR2/ALX to evoke canonical responses. SAA interacted/activated the I and the II extracellular loops of FPR2/ALX, whereas the compound 43 suffices the I extracellular loop. In summary, the FPR2/AnxA1 pathway exerts a protective role in AMI. AnxA1 mimetic that activated selective FPR2/ALX domains can be synthetize to prevent tissue damage caused by AMI.en_US
dc.description.sponsorshipfunding received from the Medical Research Council.en_US
dc.language.isoenen_US
dc.publisherQueen Mary University of Londonen_US
dc.subjectAcute Myocardial Infarctionen_US
dc.subjectinflammatory responseen_US
dc.subjectLipid mediatorsen_US
dc.subjectAcute Inflammation and Resolutionen_US
dc.subjectFormyl Peptide Receptor familyen_US
dc.subjectGFP EXPRESSIONen_US
dc.titleEXPRESSION AND FUNCTION OF THE FORMYL PEPTIDE RECEPTOR 2 IN EXPERIMENTAL MYOCARDIAL INFARCTen_US
dc.typeThesisen_US


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    Theses Awarded by Queen Mary University of London

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