Hypertension accelerated experimental abdominal aortic aneurysm through upregulation of nuclear factor kappaB and Ets.
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.
Shiraya
Suguru
S
Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Suita, Japan.
Miwa
Ken
K
Aoki
Motokuni
M
Miyake
Takashi
T
Oishi
Masako
M
Kataoka
Kazusaburo
K
Ohgi
Shigetsugu
S
Ogihara
Toshio
T
Kaneda
Yasufumi
Y
Morishita
Ryuichi
R
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
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