|Bena, S. 2014. EXPRESSION AND FUNCTION OF THE FORMYL PEPTIDE RECEPTOR 2 IN EXPERIMENTAL MYOCARDIAL INFARCT. Queen Mary University of London
|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
|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,
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.
|funding received from the Medical Research Council.
|Queen Mary University of London
|Acute Myocardial Infarction
|Acute Inflammation and Resolution
|Formyl Peptide Receptor family
|EXPRESSION AND FUNCTION OF THE FORMYL PEPTIDE RECEPTOR 2 IN EXPERIMENTAL MYOCARDIAL INFARCT