Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta.
The proinflammatory cytokine IL-18 was investigated for its role in human myocardial function. An ischemia/reperfusion (I/R) model of suprafused human atrial myocardium was used to assess myocardial contractile force. Addition of IL-18 binding protein (IL-18BP), the constitutive inhibitor of IL-18 activity, to the perifusate during and after I/R resulted in improved contractile function after I/R from 35% of control to 76% with IL-18BP. IL-18BP treatment also preserved intracellular tissue creatine kinase levels (by 420%). Steady-state mRNA levels for IL-18 were elevated after I/R, and the concentration of IL-18 in myocardial homogenates was increased (control, 5.8 pg/mg vs. I/R, 26 pg/mg; P < 0.01). Active IL-18 requires cleavage of its precursor form by the IL-1beta-converting enzyme (caspase 1); inhibition of caspase 1 also attenuated the depression in contractile force after I/R (from 35% of control to 75.8% in treated atrial muscle; P < 0.01). Because caspase 1 also cleaves the precursor IL-1beta, IL-1 receptor blockade was accomplished by using the IL-1 receptor antagonist. IL-1 receptor antagonist added to the perifusate also resulted in a reduction of ischemia-induced contractile dysfunction. These studies demonstrate that endogenous IL-18 and IL-1beta play a significant role in I/R-induced human myocardial injury and that inhibition of caspase 1 reduces the processing of endogenous precursors of IL-18 and IL-1beta and thereby prevents ischemia-induced myocardial dysfunction.
Department of Surgery, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
B J
BJ
Pomerantz
L L
LL
Reznikov
A H
AH
Harken
C A
CA
Dinarello
D000818:Animals; D016466:CHO Cells; D061945:Caspase Inhibitors; D003402:Creatine Kinase / Q000378:metabolism; D006224:Cricetinae; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D017202:Myocardial Ischemia / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000378:metabolism
D061945:Caspase Inhibitors; D006023:Glycoproteins; C507763:IL1RN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D020382:Interleukin-18; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C118370:interleukin-18 binding protein; D003402:Creatine Kinase