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(Hypertension. 2004;44:758.)
© 2004 American Heart Association, Inc.

Scientific Contributions

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; Masatsugu Horiuchi

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

Correspondence to Masatsugu Horiuchi, MD, PhD, FAHA, Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

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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