Lipophilic statins induce apoptosis of human vascular smooth muscle cells.
BACKGROUND
The accumulation of vascular smooth muscle cells (VSMC) in the intima is an early feature of atherosclerosis that results from a balance of migration from the media, proliferation, and eventual death (including programmed cell death) of VSMC. Several reports have described that HMG-CoA reductase inhibitors (statins) attenuate both the migration and proliferation of VSMC. However, the potential effect of statins on VSMC programmed cell death has received little attention.


METHODS
Human and rat VSMC were incubated with different concentration of statins in the presence of fetal bovine serum as a survival factor. The presence of apoptosis was evaluated by morphological criteria, flow cytometry and DNA electrophoresis.


RESULTS
Lipophilic statins induced, in a dose-dependent manner the appearance of VSMC apoptosis. The effect of statins was fully reversed by mevalonate, farnesylpyrophosphate, and geranylgeranypyrophosphate, but not by cholesterol or other mevalonate metabolites, suggesting a role for isoprenoids in VSMC apoptosis. In addition, the induction of apoptosis by statins was associated with the inhibition of prenylation of Rho B.


CONCLUSIONS
The present results suggest that protein prenylation inhibition by statins may be involved in statin-induced VSMC apoptosis. These data provide a new potential mechanism by which statins may modulate the evolution of atherosclerotic lesions.
Research Laboratories, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spain. cguijarro@fhalcorcon.es
C
C
Guijarro
L M
LM
Blanco-Colio
Z A
ZA
Massy
M P
MP
O'Donnell
B L
BL
Kasiske
W F
WF
Keane
J
J
Egido
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D017035:Pravastatin / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D019821:Simvastatin / Q000494:pharmacology
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D017035:Pravastatin