Cardiovascular Research Advance Access first published online on June 7, 2008
This version [Corrected Proof] published online on July 1, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn157
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Homocysteine modulates the effect of simvastatin on expression of ApoA-I and NF-
B/iNOS
1 Department of Human Genetics, McGill University, Montreal Children's Hospital Research Institute, 4060 Ste. Catherine West, Suite 241, Montréal, Quebec, Canada H3Z 2Z3
2 Department of Pediatrics, McGill University, Montreal Children's Hospital Research Institute, 4060 Ste. Catherine West, Suite 241, Montréal, Quebec, Canada H3Z 2Z3
* Corresponding author. Tel: +1 514 412 4358; fax: +1 514 412 4331. E-mail address: rima.rozen{at}mcgill.ca
Aims: Statins can ameliorate atherosclerosis by inhibition of cholesterol biosynthesis or by modulation of inflammation. In earlier work, we showed that homocysteine (Hcy) reduced synthesis of apolipoprotein A-I (ApoA-I). Our goal in this study was to determine whether Hcy could interfere with the ability of simvastatin to increase ApoA-I synthesis or to modify statin-dependent regulation of inflammatory factors.
Methods and results: Human HepG2 hepatocarcinoma cells and murine RAW264.7 macrophages were treated with simvastatin, with and without Hcy, to examine the expression of ApoA-I and nuclear factor-
B (NF-B) or the NF-B target, inducible nitric-oxide synthase (iNOS), respectively. Mice with methylenetetrahydrofolate reductase (Mthfr) deficiency, an animal model of hyperhomocysteinemia, were administered simvastatin (in diets or by injection) for in vivo assessment of these interactions. In HepG2 cells, Hcy reduced the statin-dependent increases in ApoA-I protein, mRNA, and ApoA-I promoter activity. In RAW264.7 macrophages, simvastatin decreased, whereas Hcy increased, the expression of pro-inflammatory NF-B protein; in the presence of both Hcy and simvastatin, the pro-inflammatory effect of Hcy prevailed. Hcy increased mRNA levels of iNOS in the macrophage line; the combination of Hcy and simvastatin resulted in a trend towards greater induction. In mouse studies, simvastatin decreased cholesterol levels, but levels of ApoA-I in Mthfr-deficient mice remained lower than those in Mthfr+/+ mice. Simvastatin injection increased iNOS protein and mRNA levels in peripheral blood of hyperhomocysteinemic Mthfr-deficient mice, but not in Mthfr+/+ mice. The drug also increased MTHFR protein in cells and mouse liver, an effect that was modified by Hcy.
Conclusion: These findings provide a link between statins and folate-dependent Hcy metabolism, and suggest that Hcy interferes with some anti-atherogenic and anti-inflammatory properties of simvastatin. Our work may have clinical relevance for hyperhomocysteinemic individuals on statin therapy.
KEYWORDS Homocysteine; Statin; Apolipoprotein AI; MTHFR; Inducible nitric-oxide synthase; Nuclear factor-B
Time for primary review: 27 days