c-Jun DNAzymes inhibit myocardial inflammation, ROS generation, infarct size, and improve cardiac function after ischemia-reperfusion injury.

Abstract

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.

METHODS AND 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.

• Authors: Xiao Luo, Hong Cai, Jun Ni, Ravinay Bhindi, Harry C Lowe, Colin N Chesterman, Levon M Khachigian
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 29 Issue 11 Pg. 1836-42 (Nov 2009) ISSN: 1524-4636 [Electronic] United States
• PMID: 19592465 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Catalytic
• Reactive Oxygen Species
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Apoptosis (physiology)
• Cells, Cultured (cytology, metabolism)
• DNA, Catalytic (metabolism)
• Disease Models, Animal
• Heart Function Tests
• Immunohistochemistry
• In Situ Nick-End Labeling
• JNK Mitogen-Activated Protein Kinases (metabolism, pharmacology)
• Myocardial Infarction (enzymology, etiology, pathology)
• Myocarditis (complications, metabolism, pathology, prevention & control)
• Myocytes, Cardiac (cytology, metabolism)
• Probability
• Random Allocation
• Reactive Oxygen Species (metabolism)
• Reference Values
• Reperfusion Injury (complications, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction