Liu SL, Li YH, Shi GY, Jiang MJ, Chang
JH, Wu HL.
Department of Biochemistry and Molecular Biology, College of Medicine,
National Cheng Kung University, Tainan, Taiwan.
BACKGROUND: Beyond lipid lowering, 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitor (statin) has been found to have
anti-inflammatory and anti-thrombotic effects. However, the genetic
expression pattern changes in atherosclerotic lesions produced
by statin are rarely studied.
METHODS: Cholesterol-fed apolipoprotein (Apo)
E-deficient mice were examined for the treatment effect of statin
on aortic gene expression. ApoE-deficient mice were fed with a
hypercholesterolemic diet started at 8 weeks of age for a total
of 22 weeks. In the statin treatment group (n=25), the ApoE-deficient
mice were treated with pravastatin (80 mg/kg/day) dissolved in
water by daily oral inoculation from 25 to 30 weeks of age. For
the control group (n=25), the ApoE-deficient mice were orally
inoculated with water only for the same period of time. The aortic
gene expression affected by pravastatin was identified using oligonucleotide
microarray technology with Agilent gene chips.
RESULTS: The total cholesterol and atherosclerotic
lesion/total aortic area were significantly lower in the pravastatin
treatment group. Microarray analysis of the expression of 20,281
murine genes in the aortas between the two groups indicated that
94 genes were significantly regulated. Thirty genes were up-regulated
and 64 genes were down-regulated. The most up-regulated genes
were troponin T3, actin alpha1, tubulin alpha1, regulator of G-protein
signaling 5 (Rgs5), stathmin-like 2 and myosin light chain kinase.
Most of them are related with cytoskeleton organization, while
Rgs5 is a G-protein signal transduction molecule. The most down-regulated
genes were adenosine deaminase, atrial natriuretic peptide, troponin
T2, FXYD domain-containing ion transport regulator 3, and glutathione
S-transferase alpha4.
CONCLUSIONS: The beneficial effect of the 6-week
statin treatment in ApoE-deficient mice is largely dependent on
its influence on the cytoskeleton organization. Our study results
might provide insight into the clinical benefits of chronic statin
treatment.
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