Oxysterol-induced apoptosis of vascular smooth muscle cells is reduced by HMG-CoA reductase inhibitor, pravastatin.
We investigated the mechanism by which 7-ketocholesterol damages vascular smooth muscle cells and the protective effect of the hydroxymethyl glutary CoA reductase inhibitor, pravastatin on it. When 7-ketocholesterol (50 micromol/L) was added to cultured human vascular smooth muscle cells, the extent of cell detachment increased and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling was positive. DNA extracted from the smooth muscle cells exposed to 7-ketocholesterol showed a ladder pattern on agarose electrophoresis. The fragmented DNA also increased in smooth muscle cells incubated with 7-ketocholesterol dose-dependently. In the presence of pravastatin, the cell detachment induced by 7-ketocholesterol was inhibited and the amount of fragmented DNA decreased significantly. These effects of pravastatin were inhibited by mevalonate. The results suggest that 7-ketocholesterol-induced apoptosis of vascular smooth muscle cells is inhibited by pravastatin, and mevalonate acts as a trigger of the apoptosis.
Miyashita
Yoh
Y
Center of Diabetes, Endocrinology & Metabolism, Sakura Hospital, Toho University School of Medicine, Chiba, Japan. mumon@sf6.so-net.ne.jp
Ozaki
Hiroshi
H
Koide
Nobukiyo
N
Otsuka
Masaki
M
Oyama
Tomokazu
T
Itoh
Yoshiaki
Y
Mastuzaka
Teruyo
T
Shirai
Kohji
K
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000494:pharmacology; D003331:Coronary Vessels / Q000166:cytology; D004247:DNA / Q000032:analysis; D053938:DNA Fragmentation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007653:Ketocholesterols / Q000633:toxicity*; D008798:Mevalonic Acid / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D017035:Pravastatin / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D007653:Ketocholesterols; D004247:DNA; D002784:Cholesterol; D017035:Pravastatin; C003001:7-ketocholesterol; D008798:Mevalonic Acid