Dual Effect of Lovastatin and Simvastatin on LDL-Macrophage Interaction

Abstract

Lovastatin and simvastatin which are very potent cellular cholesterol biosynthesis Inhibitors, significantly affect the plasma lipoprotein concentration.After incubation of plasma with 14 C-labelled compounds, radioactivity was found in all lipoprotein fractions but mainly (40%) in high density lipoprotein (HOL), and in the lipoprotein-deficient plasma fraction (20-30%). Dr g-treated lipoproteins showed reduced electrophoretic mobility on cellulose acetate in comparison with control lipoproteins. The lovastatin-treated low density lipoprotein (LDL) displayed 28% increased fluidity in comparison with control LDL. The immunoreactivity of drug-treated LDL with monoclonal antibody directed towards the LDL receptor binding domains (B1B6) was significantly less than that of control LDL, suggesting reduced binding to the LDL receptor. When drug-treated LDL was incubated with J-774 A. l macrophage-like cell line, its binding (at 4 °C) was 28% less than that of control LDL, whereas a substantial increase in the cellular cholesterol esterification rate (by 83% with lovastatin and by 67% with simvastatin) was noted. Similarly, the degradation of lovastatin and simvastatin-treated LDL by macrophages was 87 -89% greater than that of control LDL. The "apparent V max " for the macrophage degradation of lovastatin-treated LDL was 70% greater than that for control LDL. Thus, both drugs may have a dual effect on the macrophage uptake of LDL; they may increase the number of LDL receptors on the cell surface, but they may also reduce the affinity of LDL for its receptor, the former being the major effect. If the in vitro changes caused by drug-treated LDL also occur in vivo, then the cellular uptake of LDL and plasma cholesterol concentration could be determined by the magnitude of each of the opposing effects of the drugs.

Pravastatin inhibits cellular cholesterol synthesis and increases low density lipoprotein receptor activity in macrophages: in vitro and in vivo studies.

“…The relative contribution of this route, compared with direct binding of the drug to the macrophages, in the cellular uptake of pravastatin is not known. Unlike lovastatin and simvastatin [27], incubation of pravastatin with LDL had no effect on the lipoprotein electrophoretic mobility or immunoreactibility with mAb B1B6 (which reacts with the LDL receptor binding domains on the LDL apo B100). Pravastatin, unlike simvastatin, also did not affect LDL composition [27].…”

“…Unlike lovastatin and simvastatin [27], incubation of pravastatin with LDL had no effect on the lipoprotein electrophoretic mobility or immunoreactibility with mAb B1B6 (which reacts with the LDL receptor binding domains on the LDL apo B100). Pravastatin, unlike simvastatin, also did not affect LDL composition [27]. LDL may well be an important carrier of statin agents in the circulation [29].…”

Mycobacterium lepraeintracellular survival relies on cholesterol accumulation in infected macrophages: a potential target for new drugs for leprosy treatment

“…Moreover, a recent report has suggested that clofazimine, one of the drugs that compose the WHO‐MDT regimen for leprosy treatment, exerts its microbicidal activity via the decreasing LD accumulation in infected cells (Degang et al ., ). Interestingly, besides its classical mechanistic action of inhibiting the HMGCR, lovastatin was able to decrease LDL‐Cho uptake in ML‐infected macrophages, corroborating with the literature data (Aviram et al ., ). Of note, lovastatin was shown to more drastically affect ML viability than BCG viability.…”

Pleiotrophe Effekte von Statinen (3-Hydroxy-3-Methylglutaryl-Coenzym A-Reduktasehemmer)

“…endotheliale Monozytenadhäsion [29] und die Cholesterin-Aufnahme und Cholesterin-Anreicherung in Makrophagen reduziert wird [30,31]. Obwohl die Anzahl der LDL-Rezeptoren auf der Makrophagenoberfläche durch Statine erhöht wird, nimmt deren Affinität zum LDL ab [32]. Des weiteren wird die Bildung von Cholesterinestern und konsekutiv deren Aufnahme durch Makrophagen mittels des Enzyms Acyl-CoA: Cholesterin Acyltransferase (ACAT) gestört [33].…”