Rosuvastatin prevents endothelial cell death and reduces atherosclerotic lesion formation in ApoE-deficient mice.
Accumulating evidence suggests that statins have beneficial effects which are independent of their lipid-lowering actions, on vascular cells. Here, we investigated whether the HMG-CoA reductase inhibitor rosuvastatin can inhibit atherosclerotic lesion development with favorable effects on endothelial cells in ApoE-deficient mice. Rosuvastatin rapidly phosphorylated Akt and endothelial nitric oxide synthase (eNOS) in human endothelial cells. Endothelial cell death induced by serum starvation was significantly inhibited by rosuvastatin (percent cell death; 45.9+/-2.4% vs. 37.3+/-1.1%, p<0.05). Eight-week-old ApoE-deficient mice were orally administered vehicle or rosuvastatin at a dose of 20mg/kg/day for 24 weeks. There was no significant difference in cholesterol profile. Rosuvastatin preserved endothelial lining at the aortic root (CD31-positive luminal side; 63.8+/-2.8% vs. 81.7+/-3.9%, p<0.05). En face Sudan IV staining of aorta revealed that rosuvastatin significantly decreased the atherosclerotic area (21.9+/-2.9% vs. 11.9+/-1.9%, p<0.05). Lipid deposition at the atherosclerotic area was also suppressed by rosuvastatin with more stabilized morphologic features as determined by oil red O staining (3.4+/-0.4% vs. 1.7+/-0.4%, p<0.05). Our findings indicate that rosuvastatin protects endothelial cells from death with phosphorylation of Akt and eNOS. These effects may contribute, at least in part, to the anti-atherosclerotic effects of rosuvastatin.
Enomoto
Soichiro
S
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Sata
Masataka
M
Fukuda
Daiju
D
Nakamura
Kazuto
K
Nagai
Ryozo
R
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology*; D016923:Cell Death; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*
D001057:Apolipoproteins E; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt