Nonenzymatic Mechanism of Statins in Modulating Cholesterol Particles Formation.
Statin drugs are leading medication prescribed for treatment of dyslipidemic patients aimed at preventing both primary and secondary incidences of atherosclerosis-related cardiovascular events. Statin drugs competitively inhibit HMG-CoA reductase enzyme activity, thereby inhibiting cell-mediated cholesterol synthesis and reducing the low-density lipoprotein (LDL) cholesterol concentration of plasma. Conversely, the mechanism by which statins increase high-density lipoprotein (HDL) cholesterol concentration of plasma is not well understood. The plaque array method was used to examine the effect of statins on in vitro cholesterol particle formation. We observed that statins induced high-density cholesterol particle formation in buffer solution with or without the addition of human serum. Besides, simvastatin and lovastatin in their inactive pro-drug forms modulate formation of LDL and HDL cholesterol particles, indicating a novel nonenzymatic mechanism of statins. In a pilot study, screening of serum samples in the assay showed variation among patient samples in response to different statins. Specifically, screening of 50 serum samples with high cholesterol and statin treatment, compared with standard LDL-based measurement of statin efficacy, showed a good correlation for simvastatin (88%) and atorvastatin (84%). Taken together, our data indicate that statins, in addition to inhibiting enzyme-mediated cholesterol synthesis, have the capability to nonenzymatically modulate formation of LDL and HDL cholesterol particles in vitro. Similar interactions occurring in serum may provide a means to alter cholesterol particle formation in vivo.
Plaxgen Inc., Fremont, California. Electronic address: shan@plaxgen.com.
Shanmugavel
S
Madasamy
Plaxgen Inc., Fremont, California.
Umadevi
U
Shivasubramani
Plaxgen Inc., Fremont, California.
Jasmine
J
Villanueva
Stanford Shared FACS Facility, School of Medicine, Beckman Center, Stanford University, Stanford, California.
Marty
M
Bigos
Molecular Medicine Research Institute, Sunnyvale, California.
Edward P
EP
Amento
Plaxgen Inc., Fremont, California; San Francisco General Hospital, University of California, San Francisco, California.
Alan H B
AH
Wu
D000069059:Atorvastatin / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000187:drug effects* / Q000378:metabolism; D008078:Cholesterol, LDL / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000188:drug therapy*; D066298:In Vitro Techniques; D008148:Lovastatin / Q000494:pharmacology; D010865:Pilot Projects; D011355:Prodrugs / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011355:Prodrugs; D002784:Cholesterol; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin