dc.contributor.author | Bena, Stefania | |
dc.date.accessioned | 2015-07-15T14:53:49Z | |
dc.date.available | 2015-07-15T14:53:49Z | |
dc.date.issued | 2014-09-28 | |
dc.identifier.citation | Bena, S. 2014. EXPRESSION AND FUNCTION OF THE FORMYL PEPTIDE RECEPTOR 2 IN EXPERIMENTAL MYOCARDIAL INFARCT. Queen Mary University of London | en_US |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/7905 | |
dc.description | The 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 author | en_US |
dc.description.abstract | In 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.sponsorship | funding received from the Medical Research Council. | en_US |
dc.language.iso | en | en_US |
dc.publisher | Queen Mary University of London | en_US |
dc.subject | Acute Myocardial Infarction | en_US |
dc.subject | inflammatory response | en_US |
dc.subject | Lipid mediators | en_US |
dc.subject | Acute Inflammation and Resolution | en_US |
dc.subject | Formyl Peptide Receptor family | en_US |
dc.subject | GFP EXPRESSION | en_US |
dc.title | EXPRESSION AND FUNCTION OF THE FORMYL PEPTIDE RECEPTOR 2 IN EXPERIMENTAL MYOCARDIAL INFARCT | en_US |
dc.type | Thesis | en_US |