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.
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: E Madison Sullivan; Edward Ross Pennington; William D Green; Melinda A Beck; David A Brown; Saame Raza Shaikh Journal: Adv Nutr Date: 2018-05-01 Impact factor: 8.701
Authors: Inthirai Somasuntharam; Kevin Yehl; Sheridan L Carroll; Joshua T Maxwell; Mario D Martinez; Pao-Lin Che; Milton E Brown; Khalid Salaita; Michael E Davis Journal: Biomaterials Date: 2015-12-21 Impact factor: 12.479
Authors: Eun-Ae Cho; Fergal J Moloney; Hong Cai; Annie Au-Yeung; Carlos China; Richard A Scolyer; Benafsha Yosufi; Mark J Raftery; Jason Z Deng; Stephen W Morton; Paula T Hammond; Hendrik-Tobias Arkenau; Diona L Damian; Douglas J Francis; Colin N Chesterman; Ross St C Barnetson; Gary M Halliday; Levon M Khachigian Journal: Lancet Date: 2013-05-07 Impact factor: 79.321
Authors: Laurel A Grisanti; Christopher J Traynham; Ashley A Repas; Erhe Gao; Walter J Koch; Douglas G Tilley Journal: Proc Natl Acad Sci U S A Date: 2016-12-12 Impact factor: 11.205