Thursday, January 5, 2012
Figure 1. Inflammasome activation pathway. Acute myocardial infarction (AMI) causes
the release of danger signals including damage-associated molecular pattern
molecules (DAMPs) and ATP in response to tissue damage, cell death and lack of
blood and nutrient supply to the heart [a].
ATP activates purinergic receptor P2X ligand-gated ion channel 7 (P2RX7; P2X7), causing the
channel to open, resulting in K+ efflux from the cell [b(1)]. According to the findings from Mezzaroma
al., this process occurs
in cardiomyocytes. Extracellular K+ activates the membrane receptor pannexin 1
(PANX1), opening the channel and allowing
transport of DAMPs into the cardiomyocyte [b(2)].
serve as direct activating ligands for NLR family pyrin domain
(NLRP3; NALP3). Activation of NLRP3 induces PYD and CARD domain containing (PYCARD; ASC) recruitment and inflammasome formation [b(3)]. Inflammasome formation causes cleavage
of procaspase-1 into IL-1 b-converting enzyme (CASP1), causing downstream activation of
inflammatory cytokines including IL-1b
and IL-18 [b(4)].
of IL-1b and other cytokines from cardiomyocytes
ultimately induces immune cell recruitment to the heart, inflammation and cardiac
al. show that antagonizing
P2X7 prevents inflammasome formation and cardiac remodeling (i). IL-1b inhibitors block immune cell recruitment downstream,
blocking some cardiovascular inflammation and remodeling (ii).