PROAPOPTOTIC EFFECT OF ATORVASTATIN ON STIMULATED RABBIT SMOOTH-MUSCLE CELLS

The in vitro and in vivo activity of atorvastatin and other 3-hydroxy- 3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors (fluvastatin , pravastatin and simvastatin) has been investigated. Atorvastatin, fl uvastatin, pravastatin and simvastatin caused a significant and dose-d ependent (0.1-50 mu M) reduction in cell multiplication of vascular sm ooth muscle cells (SMC) in cultures associated with the retardation of cycling cells in the G1 and G2/M compartments at 24 h, a phenomenon l eading to apoptosis (programmed cell death) in several experimental in vitro models. The effects on the cell cycle resulted in a strong inhi bition of cell proliferation at 48 h, followed by apoptosis when incub ation was prolonged to 72 h as assessed by nuclei morphology and cytof luorimetric analysis of DNA. The apoptotic effect observed for the sta tins is completely prevented by the addition of exogenous mevalonate a t a 100 mu M concentration. In vivo SMC proliferation was stimulated b y applying a silastic collar to the outside surface of carotid arterie s in normocholesterolemic rabbits in the presence of an anatomically i ntact endothelium. The positioning of the collar promoted apoptosis in control vessels as assessed by Terminal Deoxynucleotidyl Transferase- dUTP-Biotin Nick-End Labeling (TUNEL) assay. The pre-treatment with 5 mg kg(-1) per day of atorvastatin before collar insertion strongly inc reased the number of TUNEL-positive cells, suggesting a pro-apoptotic effect of HMGCoA reductase inhibitors also in vivo, even though cell D NA rearrangement still needs to be excluded. No apoptotic signal was d etectable in sham operated arteries with no collar in either control o r atorvastatin-treated rabbits. These data indicate that HMGCoA reduct ase inhibitors effect on the arterial wall may involve the modulation of both cell proliferation and programmed cell deaths supporting a pos sible role of statins in the prevention of early lesion and restenosis . (C) 1997 The Italian Pharmacological Society.