Inhibition of experimental abdominal aortic aneurysm in a rat model by the angiotensin receptor blocker valsartan.
Angiotensin (Ang) II exerts direct effects on the arterial wall to influence atherosclerosis and aneurysm development with the induction of vascular inflammation. Therefore, we examined the hypothesis that the inhibition of Ang II would decrease the expansion of abdominal aortic aneurysm (AAA) in a rat model. We used the Ang II receptor blocker (ARB) valsartan to inhibit the effect of Ang II. Additionally, we employed a dosage of valsartan (1 mg/ kg/day) that does not affect blood pressure, to avoid the effect of blood pressure lowering. Notably, progression of elastase-induced AAA was inhibited in rats treated with valsartan (P< or =0.05). To clarify the mechanism, we focused on matrix metalloproteases (MMPs) and inflammatory related factors. Western blot analysis demonstrated that the expression of MMPs was significantly decreased in an AAA model treated with continuous ARB infusion compared to an AAA model treated with vehicle (P< or =0.05), through suppression of nuclear factor kappaB activation (P< or =0.05). Consistently, valsartan significantly inhibited infiltration of macrophages into the aortic wall, accompanied by a reduction of protein expression of intercellular adhesion molecule-1. Importantly, the inhibitory effect of valsartan on MMP-2 and MMP-9 expression was also confirmed using isolated peritoneal macrophages from a rat AAA model. Moreover, treatment with valsartan protected against the destruction of elastic fibers. Overall, the present study demonstrated that treatment with valsartan, significantly prevented the progression of experimental AAA in a rat model. These data suggest that blockade of Ang II has an inhibitory effect on the development of AAA, independent of its antihypertensive effect.
Fujiwara
Yoshikazu
Y
Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Suita, Japan.
Shiraya
Suguru
S
Miyake
Takashi
T
Yamakawa
Satoshi
S
Aoki
Motokuni
M
Makino
Hirofumi
H
Nishimura
Motonobu
M
Morishita
Ryuichi
R
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001012:Aorta, Abdominal / Q000000981:diagnostic imaging / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D010196:Pancreatic Elastase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014463:Ultrasonography; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D016328:NF-kappa B; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D014633:Valine