Abstract 20701: Formation of the Inflammasome in the Mouse Heart During Acute Myocardial Infarction Promotes Adverse Cardiac Remodeling
Background: Tissue damage during acute myocardial infarction (AMI) initiates an intense inflammatory response promoting further dysfunction and heart failure. Cryopyrin (NLRP3) is activated in response to tissue injury and leads to the formation of the apoptosis speck-like protein containing a caspase-recruitment domain (ASC) inflammasome, a multiprotein complex necessary for caspase-1 activation and interleukin-1β release. Whether the inflammasome forms in the myocardium during AMI is unknown.
Methods: CD-1 male mice underwent permanent surgical ligation of the left coronary artery to induce AMI (N=6 per group). We measured ASC expression and caspase-1 tissue activity after AMI and assessed for the formation of ASC aggregates in cells indicative of the formation of the inflammasome in the heart. We then tested whether caspase-1 tissue activity and ASC expression were affected by downregulation of key components of the inflammasome by using small interfering RNA (siRNA) targeted to P2X7 membrane receptor and cryopyrin. Finally, we tested whether inhibition of the P2X7 receptor (using a pharmacologic inhibitor [PPADS]) could prevent adverse cardiac remodeling following AMI.
Results: Caspase-1 activity was increased as early as 3 hours and up to 14 days, with a peak at 72 hours. Increased ASC expression was found at Western blot and ASC aggregates were found in the granulation tissue as well as cardiomyocytes in the peri-infarct myocardium 3 and 7 days after AMI with only minimal expression in the remote myocardium and no expression in the sham-operated mice (P<0.05). Increased ASC expression in cardiomyocytes was confirmed in vitro using HL-1 cardiomyocytes treated with nigericin, an inducer of the inflammasome. P2X7- and cryopyrin-targeted siRNA lead to reduced ASC expression and caspase-1 activity after AMI (P<0.05). Treatment with PPADS for 1 week after AMI led to a smaller infarct size and a smaller increase in left ventricular end-diastolic and end-systolic diameters (P<0.05).
Conclusions: The ASC inflammasome is formed in the heart during AMI through P2X7-mediated activation of cryopyrin, and promotes adverse cardiac remodeling. P2X7, cryopyrin and the inflammasome may represent novel targets for intervention in AMI and heart failure.
- © 2010 by American Heart Association, Inc.