Regression of abdominal aortic aneurysms by simultaneous inhibition of nuclear factor kappaB and ets in a rabbit model.
Because current therapy to treat abdominal aortic aneurysm (AAA), and particularly to manage small AAA, is limited to elective surgical repair, we explored less invasive molecular therapy by simultaneous inhibition of the transcription factors nuclear factor (NF)kappaB and ets using a decoy strategy. Both NFkappaB and ets were shown to be markedly activated in human AAA. In addition, NFkappaB- and ets-positive cells were increased in the aneurysm wall, and a part of the expression of NFkappaB and ets was detected in migrating macrophages. Thus, we used chimeric decoy oligodeoxynucleotides (ODNs) containing consensus sequences of both NFkappaB and ets binding sites to treat AAA. Inhibitory effects of chimeric decoy ODNs on matrix metalloproteinase-1 and -9 expression were confirmed by ex vivo experiments using a human aorta organ culture. To examine the regressive effect in a rabbit already-formed AAA model, transfection by wrapping a delivery sheet containing chimeric decoy ODNs around the aneurysm was performed 1 week after incubation with elastase. Importantly, treatment with chimeric decoy ODNs significantly decreased the size of AAA. Interestingly, significant preservation of elastic fibers was observed with chimeric decoy ODN treatment, accompanied by a reduction of matrix metalloproteinase-2 and -9 and induction of macrophage apoptosis. Regression of AAA was also associated with an increase in elastin and collagen type I and III synthesis in the aneurysm wall. Minimally invasive molecular therapy targeted to the inhibition of NFkappaB and ets is expected to be useful for AAA through the rebalance of matrix synthesis and degradation.
Miyake
Takashi
T
Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
Aoki
Motokuni
M
Masaki
Hisao
H
Kawasaki
Tomio
T
Oishi
Masako
M
Kataoka
Kazusaburo
K
Ogihara
Toshio
T
Kaneda
Yasufumi
Y
Morishita
Ryuichi
R
D000818:Animals; D001011:Aorta; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D003094:Collagen / Q000096:biosynthesis; D016384:Consensus Sequence; D004195:Disease Models, Animal; D004549:Elastin / Q000096:biosynthesis; D006801:Humans; D008264:Macrophages / Q000166:cytology; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects; D018716:Molecular Mimicry; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D050784:Proto-Oncogene Protein c-ets-1 / Q000037:antagonists & inhibitors*; D011817:Rabbits
D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D050784:Proto-Oncogene Protein c-ets-1; D003094:Collagen; D004549:Elastin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9