A HMG-CoA reductase inhibitor possesses a potent anti-atherosclerotic effect other than serum lipid lowering effects - The relevance of endothelial nitric oxide synthase and superoxide anion scavenging action

Daigo Sumi, Toshio Hayashi, Navin Kumar Thakur, Muthuvel Jayachandran, Yukako Asai, Hatsuyo Kano, Hisako Matsui, Akihisa Iguchi

Research output: Contribution to journalArticle

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Abstract

We have determined whether the anti-atherosclerotic effect of a 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (fluvastatin) is mediated through nitric oxide (NO) as well as affecting plasma lipids. NO related vascular responses, endothelial nitric oxide synthase (eNOS) mRNA and superoxide anion (O2-) release were examined in vascular walls of oophorectomized female rabbits fed 0.5% cholesterol chow for 12 weeks with or without fluvastatin (2 mg/kg per day). Serum lipid profile was not different between two groups. NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by NG-monomethyl-L-arginine acetate (L-NMA); nitric oxide synthase inhibitor were all improved by fluvastatin treatment. Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits' arteries. Fluvastatin treatment increased cyclic GMP concentration in aorta of rabbits. eNOS mRNA expression and O2- release were measured in aorta using competitive reverse transcription-polymerase chain reaction (RT-PCR) and with lucigenin analogue, 2-methyl-3,7-dihydroimidazol [1,2-a]pyrazine-3-one (MCLA) chemiluminescence methods. eNOS mRNA in the endothelial cells of aorta was significantly up-regulated and O2- production was significantly reduced in fluvastatin treated rabbit aorta. Anti-macrophage staining area, but not anti-smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment. Conclusion, fluvastatin, a HMG-CoA reductase inhibitor, retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up-regulation of eNOS mRNA and decrease of O2- production in vascular endothelial cells, and this means that part of the anti-atherosclerotic effect of fluvastatin may be due to nonlipid factors.

Original languageEnglish (US)
Pages (from-to)347-357
Number of pages11
JournalAtherosclerosis
Volume155
Issue number2
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

fluvastatin
Nitric Oxide Synthase Type III
Superoxides
Oxidoreductases
Lipids
Aorta
Nitric Oxide
Serum
Rabbits
Messenger RNA
Blood Vessels
Endothelial Cells
Pyrazines
omega-N-Methylarginine
Calcium Ionophores
glutaryl-coenzyme A
Cyclic GMP
Calcimycin
Nitroglycerin
Luminescence

Keywords

  • Atherosclerosis
  • Endothelial nitric oxide synthase
  • HMG-CoA reductase inhibitor
  • Nitric oxide
  • Superoxide anion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

A HMG-CoA reductase inhibitor possesses a potent anti-atherosclerotic effect other than serum lipid lowering effects - The relevance of endothelial nitric oxide synthase and superoxide anion scavenging action. / Sumi, Daigo; Hayashi, Toshio; Thakur, Navin Kumar; Jayachandran, Muthuvel; Asai, Yukako; Kano, Hatsuyo; Matsui, Hisako; Iguchi, Akihisa.

In: Atherosclerosis, Vol. 155, No. 2, 2001, p. 347-357.

Research output: Contribution to journalArticle

Sumi, Daigo ; Hayashi, Toshio ; Thakur, Navin Kumar ; Jayachandran, Muthuvel ; Asai, Yukako ; Kano, Hatsuyo ; Matsui, Hisako ; Iguchi, Akihisa. / A HMG-CoA reductase inhibitor possesses a potent anti-atherosclerotic effect other than serum lipid lowering effects - The relevance of endothelial nitric oxide synthase and superoxide anion scavenging action. In: Atherosclerosis. 2001 ; Vol. 155, No. 2. pp. 347-357.
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AU - Thakur, Navin Kumar

AU - Jayachandran, Muthuvel

AU - Asai, Yukako

AU - Kano, Hatsuyo

AU - Matsui, Hisako

AU - Iguchi, Akihisa

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AB - We have determined whether the anti-atherosclerotic effect of a 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (fluvastatin) is mediated through nitric oxide (NO) as well as affecting plasma lipids. NO related vascular responses, endothelial nitric oxide synthase (eNOS) mRNA and superoxide anion (O2-) release were examined in vascular walls of oophorectomized female rabbits fed 0.5% cholesterol chow for 12 weeks with or without fluvastatin (2 mg/kg per day). Serum lipid profile was not different between two groups. NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by NG-monomethyl-L-arginine acetate (L-NMA); nitric oxide synthase inhibitor were all improved by fluvastatin treatment. Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits' arteries. Fluvastatin treatment increased cyclic GMP concentration in aorta of rabbits. eNOS mRNA expression and O2- release were measured in aorta using competitive reverse transcription-polymerase chain reaction (RT-PCR) and with lucigenin analogue, 2-methyl-3,7-dihydroimidazol [1,2-a]pyrazine-3-one (MCLA) chemiluminescence methods. eNOS mRNA in the endothelial cells of aorta was significantly up-regulated and O2- production was significantly reduced in fluvastatin treated rabbit aorta. Anti-macrophage staining area, but not anti-smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment. Conclusion, fluvastatin, a HMG-CoA reductase inhibitor, retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up-regulation of eNOS mRNA and decrease of O2- production in vascular endothelial cells, and this means that part of the anti-atherosclerotic effect of fluvastatin may be due to nonlipid factors.

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