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

Abstract

1 Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) inhibitor, is a highly selective inhibitor of hepatic cholesterol synthesis. We studied the in vivo and in vitro effects of pravastatin on macrophage cholesterol metabolism. 2 The effects of incubating pravastatin with human monocyte derived macrophages (HMDM), mouse peritoneal macrophages (MPM) and a J-774 A.1 macrophagelike cell line, on macrophage cholesterol synthesis, cellular degradation of native low density lipoprotein (LDL) and modified LDL, cholesterol efflux from these cells and the cholesterol esterification rate were determined. 3 Pravastatin was administered either as one 40 mg dose or 40 mg daily for 8 weeks to normocholesterolaemic and hypercholesterolaemic individuals. The effects on cholesterol synthesis and degradation in monocytes derived from these subjects were studied. 4 In vitro, pravastatin resulted in a dose-dependent inhibition of macrophage cholesterol synthesis. Cellular degradation of native LDL increased by 119% in the presence of 0.1 mg ml-' pravastatin. Degradation of both acetyl LDL and oxidized LDL was unaffected. Small concentrations of pravastatin (up to 0.19 ,ug ml-') increased the cellular cholesterol esterification rate after incubation with LDL, but higher concentrations resulted in an inhibition of the esterification. 5 Single dose pravastatin administration caused a reduction in cholesterol synthesis by the subjects own HMDM by 62% and 47% in normocholesterolaemic and hypercholesterolaemic individuals, respectively. Chronic administration resulted in a 55% inhibition of cholesterol synthesis and a 57% increase in LDL degradation. 6 The results indicate that the selective uptake of pravastatin shown for hepatocytes can be extended to macrophages. Pravastatin can inhibit cholesterol accumulation in cells of the arterial wall and by so doing exhibits an additional anti-atherogenic characteristic.

Lovastatin Decreases the Receptor-Mediated Degradation of Acetylated and Oxidized LDLs in Human Blood Monocytes During the Early Stage of Differentiation Into Macrophages

“…In agreement with previous studies in human monocyte-derived macrophages, 12,13 LOV increased the receptor-specific degradation of nat LDL. This effect was observed when LOV was given to freshly seeded cells during their spontaneous differentiation to adherent macrophages, as well as in matured macrophages allowed to differentiate under control conditions before LOV treatment.…”

“…12 The lower concentration of the drug used and the longer cultivation periods may explain the lack of effect in this study. On the other hand, our results are similar to the only other study on cultured human monocytes, where a 30%, but statistically insignificant, decrease in acetyl LDL degradation after a 2-day incubation with 13 mol/L mevastatin was observed.…”

“…11 Parallel to their action in the liver, HMG-CoA reductase inhibitors have been shown to suppress cellular cholesterol synthesis and to stimulate the receptor-mediated uptake of LDL in HMDMs. [12][13][14] Their effect on the uptake and degradation of modified lipoproteins is less well established. Two earlier studies in HMDM detected no significant effects of HMG-CoA reductase inhibitors on the metabolism of modified LDL.…”

Pravastatin Protection from Cold Stress in Myocardium of Rats.

“…41) In this way, it can inhibit the interaction between platelets and fibrinogen and reduce the expression of diverse agents involved in the coagulation process. 42) Pravastatin has anti-inflammatory effects, and promotes a blockade of macrophage activation 43) and the formation of foam cells. 43,44) More recently it was demonstrated that the drug promotes in vitro inhibition of PDGF and also affects the transduction intermediated by angiotensin II through the suppression of two proto-oncogenes, c-jun and c-fos, 45) indicating the possibility of inducing a regression of myocardial hypertrophy through the blockade of independent signaling in the reduction of cholesterol.…”

“…42) Pravastatin has anti-inflammatory effects, and promotes a blockade of macrophage activation 43) and the formation of foam cells. 43,44) More recently it was demonstrated that the drug promotes in vitro inhibition of PDGF and also affects the transduction intermediated by angiotensin II through the suppression of two proto-oncogenes, c-jun and c-fos, 45) indicating the possibility of inducing a regression of myocardial hypertrophy through the blockade of independent signaling in the reduction of cholesterol. 46) The protection of cardiomyocytes by pravastatin in this study most likely occurred due to its action on the modulation of vascular relaxation mediated by the endothelium.…”