title: Hypertension accelerated experimental abdominal aortic aneurysm through upregulation of nuclear factor kappaB and Ets.
abstract: In this study, we focused on the effect of hypertension on the transcription factors nuclear factor kappaB (NFkappaB) and ets in the mechanisms of abdominal aortic aneurysm (AAA), and we investigated how hypertension affects the progression of AAA. AAA was produced by elastase perfusion in hypertensive rats and normotensive rats. The size of AAA rapidly increased in hypertensive rats as compared with normotensive rats. Western blot analysis demonstrated that the expression of matrix metalloproteinase (MMP)-2, -3 , -9, and -12, as well as intercellular adhesion molecule, was increased in hypertensive AAA rats, accompanied by upregulation of NFkappaB and ets. Moreover, in situ zymography showed that the activity of MMPs was increased in the aorta of a hypertensive AAA model as compared with that in a normotensive AAA model. Interestingly, transfection of chimeric decoy oligodeoxynucleotide (ODN) resulted in significant inhibition of aortic dilatation both in normotensive and hypertensive rats at 4 weeks after transfection. Destruction of elastic fibers was also significantly inhibited by transfection of chimeric decoy ODN in both hypertensive rats and normotensive rats. The expression of MMP-2, -3, -9, and -12, as well as intercellular adhesion molecule, was significantly attenuated by the chimeric decoy ODN, accompanied by inhibition of the migration of macrophages. Also, the effect of chimeric decoy ODN was confirmed in an organ culture. The present study demonstrated that hypertension accelerated the progression of experimental AAA through upregulation of NFkappaB and ets. Inhibition of NFkappaB and ets could be a novel therapeutic strategy to treat AAA in hypertensive patients.
authors.affiliation: Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Shiraya
authors.forename: Ken
authors.initials: K
authors.lastname: Miwa
authors.forename: Motokuni
authors.initials: M
authors.lastname: Aoki
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyake
authors.forename: Masako
authors.initials: M
authors.lastname: Oishi
authors.forename: Kazusaburo
authors.initials: K
authors.lastname: Kataoka
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Ohgi
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D006973:Hypertension / Q000150:complications*; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D009841:Oligonucleotides; D050783:Proto-Oncogene Proteins c-ets; D018799:Intercellular Adhesion Molecule-1; D020782:Matrix Metalloproteinases