Anti-oxidative Properties of Fluvastatin, an HMG-CoA Reductase Inhibitor, Contribute to Prevention of Atherosclerosis in Cholesterol-Fed Rabbits

Atherosclerosis. 2001 Jan;154(1):87-96. doi: 10.1016/s0021-9150(00)00468-8.

Abstract

Studies in vitro reveal that fluvastatin, an HMG-CoA reductase inhibitor, has a strong DPPH radical scavenging activity and achieves concentration-dependent inhibition of copper- and cell-induced oxidation of low-density lipoprotein (LDL). To further examine the anti-oxidative activity of fluvastatin in vivo, we elucidated the effects of chronic treatment with fluvastatin at a dose insufficient to reduce plasma cholesterol levels (2 mg/kg per day) on vasomotion and vascular oxidative stress in thoracic aortas of 0.5% cholesterol-fed rabbits. After 12 weeks of dietary treatment, aortic segments from rabbits fed cholesterol alone showed impaired endothelium-dependent relaxation responses to acetylcholine and A23187 compared to normal chow-fed rabbits in association with a significant increase in plasma total cholesterol levels. In contrast, although plasma total cholesterol levels were not different from those in control cholesterol-fed rabbits, aortic segments from fluvastatin-treated rabbits showed normal relaxation. Compared with rabbits fed cholesterol alone, fluvastatin treatment decreased susceptibility of LDL to ex vivo copper-induced oxidation, reduced vascular superoxide generation, and atheromatous plaque formation. In conclusion, the potent anti-oxidative properties of fluvastatin in addition to its cholesterol-lowering activity appear to contribute to its anti-atherosclerotic effect in vivo.

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Aorta / cytology
  • Aorta / metabolism
  • Arteriosclerosis / etiology*
  • Arteriosclerosis / prevention & control*
  • Bepridil / analogs & derivatives*
  • Biphenyl Compounds
  • Cells, Cultured
  • Cholesterol, Dietary*
  • Copper / metabolism
  • Endothelium, Vascular / physiopathology
  • Fatty Acids, Monounsaturated / pharmacology*
  • Fluvastatin
  • Free Radical Scavengers / pharmacology*
  • Free Radicals
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • In Vitro Techniques
  • Indoles / pharmacology*
  • Ions / metabolism
  • Lipids / blood
  • Lipoproteins, LDL / biosynthesis
  • Male
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / metabolism
  • Picrates*
  • Rabbits
  • Superoxides / metabolism

Substances

  • Antioxidants
  • Biphenyl Compounds
  • Cholesterol, Dietary
  • Fatty Acids, Monounsaturated
  • Free Radical Scavengers
  • Free Radicals
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Indoles
  • Ions
  • Lipids
  • Lipoproteins, LDL
  • Picrates
  • oxidized low density lipoprotein
  • Superoxides
  • Fluvastatin
  • Bepridil
  • Copper
  • 1,1-diphenyl-2-picrylhydrazyl