c-Jun DNAzymes inhibit myocardial inflammation, ROS generation, infarct size, and improve cardiac function after ischemia-reperfusion injury.
OBJECTIVE
Coronary reperfusion has been the mainstay therapy for reduced infarct size after a heart attack. However, this intervention also results in myocardial injury by initiating a marked inflammatory reaction, and new treatments are keenly sought.


RESULTS
The basic-region leucine zipper protein, c-Jun is poorly expressed in the normal myocardium and is induced within 24 hours after myocardial ischemia-reperfusion injury. Synthetic catalytic DNA molecules (DNAzymes) targeting c-Jun (Dz13) reduce infarct size in the area-at-risk (AAR) regardless of whether it is delivered intramyocardially at the initiation of ischemia or at the time of reperfusion. Dz13 attenuates neutrophil infiltration, c-Jun and ICAM-1 expression in vascular endothelium, cardiomyocyte apoptosis, and the generation of reactive oxygen species in the reperfused myocardium. It inhibits infiltration into the AAR of complement 3 (C3), C3a receptor (C3aR), membrane attack complex-1 (Mac-1), or matrix metalloproteinase-2 (MMP-2) positive inflammatory cells. Dz13 also improves cardiac function without influencing myocardial vascularity or fibrosis.


CONCLUSIONS
These findings demonstrate the regulatory role of c-Jun in the pathogenesis of myocardial inflammation and infarction following ischemia-reperfusion injury, and inhibition of this process using catalytic DNA.
Luo
Xiao
X
Centre for Vascular Research, University of New South Wales, Sydney, NSW, Australia.
Cai
Hong
H
Ni
Jun
J
Bhindi
Ravinay
R
Lowe
Harry C
HC
Chesterman
Colin N
CN
Khachigian
Levon M
LM
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D021881:DNA, Catalytic / Q000378:metabolism*; D004195:Disease Models, Animal; D006334:Heart Function Tests; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000494:pharmacology; D009203:Myocardial Infarction / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D009205:Myocarditis / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D011336:Probability; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012016:Reference Values; D015427:Reperfusion Injury / Q000150:complications* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D021881:DNA, Catalytic; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases