Human and porcine smooth muscle cells share similar proliferation dependence on the mevalonate pathway: implication for in vivo interventions in the porcine model.
Proliferation of smooth muscle cells (SMCs) plays an important role in vascular pathobiology by being involved in the development of coronary atherosclerosis and restenosis. Competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase have shown antiproliferative properties on different cell types. We have assessed the relative effectiveness of three HMG-CoA reductase inhibitors (compactin, lovastatin and pravastatin) in blocking serum-induced replication of human and porcine SMCs. No effects were seen on DNA synthesis in porcine or human SMCs at the reported therapeutic lipid-lowering concentrations. The effectiveness of statins in blocking SMC proliferation was similar in both species; the IC50 values for porcine cells were 12.2 mumol L-1, 12.6 mumol L-1 and 1.16 mmol L-1 for lovastatin, compactin and pravastatin respectively. Inhibition of SMC proliferation was reversed by addition of mevalonate but not by low-density lipoprotein (LDL)-cholesterol. Statins showed high anti-proliferative efficiency against purified growth factors involved in human restenosis (1 nmol L-1 platelet-derived growth factor (PDGF), 1 nmol L-1 epidermal growth factor (EGF), 10 U mL-1 alpha-thrombin). The porcine model seems to be a suitable system, closely resembling the human model, for assaying in vivo new strategies, formulations and delivery systems targeted to the mevalonate pathway to inhibit local SMC response to percutaneous transluminal coronary angioplasty.
Martínez-González
J
J
Cardiovascular Research Center, CSIC-Hospital de la Santa Creu i Sant Pau-UAB, Barcelona, Spain.
Badimon
L
L
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology* / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology
D000924:Anticholesteremic Agents; C012258:mevastatin; D004247:DNA; D008148:Lovastatin; D017035:Pravastatin; D008798:Mevalonic Acid