Angiotensin II receptor blocker reduces oxidative stress and attenuates hypoxia-induced left ventricular remodeling in apolipoprotein E-knockout mice.
Elevated superoxide formation in cardiac extracts of apolipoprotein E-knockout (apoE-KO) mice has been reported. In addition, we previously reported that hypoxia increased oxidative stress in the aortas of apoE-KO mice, although we did not examine the effect of hypoxia on the heart. The aim of this study was to investigate the effect of chronic hypoxia on the left ventricular (LV) remodeling in apoE-KO mice treated with or without an angiotensin II receptor blocker. Male apoE-KO mice (n=83) and wild-type mice (n=34) at 15 weeks of age were kept under hypoxic conditions (oxygen, 10.0+/-0.5%) and treated with olmesartan (3 mg/kg/day) or vehicle for 3 weeks. Although LV pressure was not changed, hypoxia caused hypertrophy of cardiomyocytes and increased interstitial fibrosis in the LV myocardium. Furthermore, nuclear factor-kappaB (NF-kappaB) and matrix metalloproteinase (MMP)-9 activities were increased in apoE-KO mice exposed to chronic hypoxia. Olmesartan effectively suppressed the 4-hydroxy-2-nonenal protein expression and NF-kappaB and MMP-9 activities, and preserved the fine structure of the LV myocardium without affecting the LV pressure. In conclusion, olmesartan reduced oxidative stress, and attenuated the hypoxia-induced LV remodeling, in part through the inhibition of NF-kappaB and MMP-9 activities, in apoE-KO mice.
Yamashita
Chika
C
Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.
Hayashi
Tetsuya
T
Mori
Tatsuhiko
T
Tazawa
Naoko
N
Kwak
Chol-Jun
CJ
Nakano
Daisuke
D
Sohmiya
Koichi
K
Okada
Yoshikatsu
Y
Kitaura
Yasushi
Y
Matsumura
Yasuo
Y
D000447:Aldehydes / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D000447:Aldehydes; D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D013777:Tetrazoles; D013481:Superoxides; C437965:olmesartan; D019255:NADPH Oxidases; D020780:Matrix Metalloproteinase 9; C027576:4-hydroxy-2-nonenal