A therapeutic dose of the lipophilic statin pitavastatin enhances oxidant-induced apoptosis in human vascular smooth muscle cells.
We examined effects of a physiologic concentration of pitavastatin (0.01 micromol/L) on oxidant-induced apoptosis in cultured human vascular smooth muscle cells (VSMCs). Apoptosis was induced in VSMCs by hydrogen peroxide (H2O2, 300 micromol/L), as evidenced by in situ nick end-labeling and scanning electron microscopy. This apoptotic response was accompanied by increased activation of mitogen-activated protein kinases (MAPKs--ie, increases in the phosphorylated forms of extracellular signal-regulated kinase (p-ERK), c-Jun N-terminal kinase (p-JNK), and p38 MAPK (p-p38 MAPK). Although pitavastatin alone did not induce VSMC death, pretreatment with pitavastatin significantly enhanced H2O2-induced apoptosis and prolonged activation of JNK and p38 MAPK (for up to 24 h) but not ERK. Expression of MAPK phosphatase-1 (MKP-1) also was upregulated by H2O2, but this was not affected by pitavastatin. The apoptosis accelerating effect was observed also in simvastatin but not in pravastatin. Treating VSMCs with mevalonate, farnesyl pyrophosphate, or geranylgeranyl pyrophosphate completely blocked the statin-induced enhancement of VSMC apoptosis, suggesting that protein prenylation is critically involved. It thus appears that pitavastatin enhances H2O2-induced VSMC apoptosis, at least in part, via increases in MAPK activation and protein prenylation, but independently of MKP-1 expression, which consequently results in reduction of VSMC population.
Tsujimoto
Akiko
A
From the Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
Takemura
Genzou
G
Mikami
Atsushi
A
Aoyama
Takuma
T
Ohno
Takamasa
T
Maruyama
Rumi
R
Nakagawa
Munehiro
M
Minatoguchi
Shinya
S
Fujiwara
Hisayoshi
H
D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D017368:Protein Prenylation; D011804:Quinolines / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C108475:pitavastatin