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Nitric oxide synthase II (NOS II) gene expression correlates with atherosclerotic intimal thickening. Preventive effects of HMG-CoA reductase inhibitors.

Abstract
HMG-CoA reductase inhibitors have been shown to be effective in primary and secondary prevention of coronary heart disease. Their mechanism of action is attributed to their cholesterol lowering activity but recent results seem to indicate additional effects related to the modulation of other processes that regulate the presentation of vascular diseases. Our objective has been to study the effects of atorvastatin and simvastatin, two HMG-CoA reductase inhibitors, on lesion composition and expression of genes involved in lesion development in a diet-induced atherosclerotic rabbit model. Both HMG-CoA reductase inhibitors were administered at identical doses of 2.5 mg/kg per day with the hyperlipemic diet for 10 weeks. Both statins significantly prevented the diet-induced increase in cholesterol levels. Relative lesion composition in fibrinogen, macrophages and smooth muscle cells was unaltered by the treatment although lesion size was reduced; therefore, both HMG-CoA reductase inhibitors reduced total amounts of fibrinogen, macrophages and smooth muscle cells (simvastatin, P < 0.05). NOS II gene expression was positively and significantly correlated with lesion size and inversely correlated with HDL plasma levels. NOS II expression was markedly downregulated in simvastatin treated animals while MCP-1 was unaltered. Therefore, HMG-CoA reductase inhibition seems to interfere with atherosclerotic lesion development by reducing intimal thickening development and the expression of the cytotoxic NOS II.
AuthorsJ Alfon, J F Guasch, M Berrozpe, L Badimon
JournalAtherosclerosis (Atherosclerosis) Vol. 145 Issue 2 Pg. 325-31 (Aug 1999) ISSN: 0021-9150 [Print] Ireland
PMID10488960 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Chemokine CCL2
  • Cholesterol, Dietary
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Pyrroles
  • Fibrinogen
  • DNA
  • Cholesterol
  • Atorvastatin
  • Simvastatin
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
Topics
  • Animals
  • Arteriosclerosis (enzymology, pathology, prevention & control)
  • Atorvastatin
  • Chemokine CCL2 (biosynthesis, genetics)
  • Cholesterol (blood)
  • Cholesterol, Dietary (toxicity)
  • DNA (biosynthesis)
  • Disease Models, Animal
  • Down-Regulation (drug effects, genetics)
  • Fibrinogen (metabolism)
  • Gene Expression (drug effects)
  • Heptanoic Acids (pharmacology)
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
  • Macrophages (metabolism, pathology)
  • Muscle, Smooth, Vascular (metabolism, pathology)
  • Nitric Oxide Synthase (genetics, metabolism)
  • Nitric Oxide Synthase Type II
  • Polymerase Chain Reaction
  • Pyrroles (pharmacology)
  • Rabbits
  • Simvastatin (pharmacology)
  • Tunica Intima (drug effects, enzymology, pathology)

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