Published Online
on September 27, 2004

A more recent version of this article appeared on November 1, 2004

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Submitted on March 11, 2004
Revised on March 31, 2004

Fluvastatin Enhances the Inhibitory Effects of a Selective AT₁ Receptor Blocker, Valsartan, on Atherosclerosis

Zhen Li; Masaru Iwai; Lan Wu; Hong-Wei Liu; Rui Chen; Toyohisa Jinno; Jun Suzuki; Masahiro Tsuda; Xin-Yu Gao; Midori Okumura; Tai-Xing Cui; and Masatsugu Horiuchi^*

From the Department of Medical Biochemistry, Ehime University School of Medicine, Ehime, Japan.

^* To whom correspondence should be addressed. E-mail: horiuchi{at}m.ehime-u.ac.jp.

Abstract--We investigated the effects of a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) on the inhibitory effects of an angiotensin II type-1 receptor (AT₁) blocker on atherosclerosis and explored cellular mechanisms. We gave apolipoprotein E null mice a high-cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition. Neither 1 mg/kg per day of valsartan nor 3 mg/kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration; however, both drugs decreased plaque area and lipid deposition after 10 weeks. We then reduced the doses of both drugs to 0.1 mg/kg per day and 1 mg/kg per day, respectively. At these doses, neither drug had an effect on atherosclerotic lesions. When both drugs were combined at these doses, a significant reduction in atherosclerotic lesions was observed. Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide phosphate oxidase subunits p22^phox and p47^phox, production of superoxide anion, the expression of monocyte chemoattractant protein-1, and intercellular adhesion molecule-1 expression were observed. These results suggest that concomitant AT₁ receptor and cholesterol biosynthesis blockade, particularly when given concomitantly, blunts oxidative stress and inflammation independent of blood pressure or cholesterol-related effects.

Key words: angiotensin • atherosclerosis • oxidative stress

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