Fluvastatin ameliorates the hyperhomocysteinemia-induced endothelial dysfunction: the antioxidative properties of fluvastatin.
BACKGROUND
Hyperhomocysteinemia induces vascular endothelial dysfunction, contributing to a predisposition to the onset and/or progression of atherosclerosis. The major mechanism suggested for the adverse effect of homocysteine on vascular function seems to involve oxidative stress. Thus, we hypothesized that the administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin, which is experimentally demonstrated to have antioxidative properties as one of its pleiotropic effects, is a useful strategy for eliminating the detrimental events induced by hyperhomocysteinemia.


RESULTS
In diet-induced hyperhomocysteinemic rats, we estimated oxidative stress and assessed endothelium-dependent vasodilatation. Hyperhomocysteinemia induced significant increases in urinary 8-isoprostaglandin F2alpha-III excretion and vascular superoxide generation, and impaired endothelium-dependent vasodilatation. Additional oral administration of the antioxidant fluvastatin or vitamin E, which normalized increased oxidative stress induced by hyperhomocysteinemia, ameliorated endothelial dysfunction.


CONCLUSIONS
Hyperhomocysteinemia, even mild to moderate, induces endothelial dysfunction through its oxidative effect. The antioxidant fluvastatin was able to cancel out the oxidative stress induced by hyperhomocysteinemia and ameliorate endothelial dysfunction. Clinical use of fluvastatin might be a potent strategy for eliminating the detrimental events induced by hyperhomocysteinemia as well as hyperlipidemia. In addition to lowering homocysteine by means of folate supplementation, administration of the antioxidants is expected to be a potentially effective anti-homocysteine therapy.
Morita
Hiroyuki
H
Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Saito
Yuichiro
Y
Ohashi
Noriko
N
Yoshikawa
Masayoshi
M
Katoh
Makoto
M
Ashida
Terunao
T
Kurihara
Hiroki
H
Nakamura
Tetsuya
T
Kurabayashi
Masahiko
M
Nagai
Ryozo
R
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology*; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000494:pharmacology*; D000077340:Fluvastatin; D020138:Hyperhomocysteinemia / Q000188:drug therapy* / Q000473:pathology*; D006949:Hyperlipidemias / Q000188:drug therapy / Q000473:pathology; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects; D014810:Vitamin E / Q000008:administration & dosage / Q000494:pharmacology
D000975:Antioxidants; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D014810:Vitamin E; D000077340:Fluvastatin