Mechanisms of inhibitory effects of cerivastatin on rat vascular smooth muscle cell growth.
The aim of this study was to clarify the mechanism(s) of an inhibitory effect of cerivastatin on cultured rat vascular smooth muscle cell (VSMC) growth. After being starved, cultured VSMCs were stimulated by 5% fetal bovine serum with either various concentrations of cerivastatin or 10-4 M of mevalonate. Cerivastatin dose-dependently decreased the values of [3H]-thymidine incorporation and cell numbers and the level of phosphorylated extracellular signal-regulated protein kinase 1/2. It also suppressed the level of proliferative cell nuclear antigen in a dose-dependent manner. These reductions were abolished by the addition of mevalonate. Similarly, the level of phosphorylated p38 was also decreased by cerivastatin. In contrast, cerivastatin dose-dependently activated the phosphorylation of both c-jun NH2-terminal protein kinase and activating transcription factor-2, and these activations were abolished by the addition of mevalonate. The levels of phosphorylated Akt and p70 S6 kinase as well as those of Bcl-2 were dose-dependently reduced by cerivastatin, and these reductions were abolished by the addition of mevalonate. Cerivastatin could dose-dependently elevate the levels of CPP32/caspase-3 activity and cytoplasmic histone-associated DNA fragments in VSMCs without causing cytotoxicity. These results indicate that cerivastatin suppresses cell survival and activates the apoptotic cellular signaling in VSMCs, suggesting that it could be effective for preventing the progression of restenosis after angioplasty.
Third Department of Internal Medicine and Department of Laboratory Medicine, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. migarasi@med.id.yamagata-u.ac.jp
Masahiko
M
Igarashi
Hiroshi
H
Yamaguchi
Akihiko
A
Hirata
Hiromi
H
Tsuchiya
Hiroshi
H
Ohnuma
Makoto
M
Tominaga
Makoto
M
Daimon
Takeo
T
Kato
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D011725:Pyridines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; C086276:cerivastatin