Influence of cholesterol-lowering on plasma membrane lipids and function.
In order to determine whether alterations in membrane or plasma lipids affect transmembrane cationic transport systems in erythrocytes and platelets, cationic fluxes and intracellular concentrations, membrane lipids, plasma lipids, lipoproteins and apolipoproteins were measured in hypercholesterolemic patients before and during administration of a HMG-CoA reductase inhibitor. After a 1-month placebo run-in period, the patients were treated double-blind either with placebo (n = 25) or with pravastatin (n = 25) for 6 months. Placebo or pravastatin 10 mg during the 1st month, 20 mg during the 2nd month and 40 mg during the additional 4 months was administered once daily in the evening. Blood was collected in the morning after an overnight fast for assay of membrane and plasma lipids and of cationic fluxes and concentrations, at the end of the placebo run-in period and after 1, 2, 3 and 6 months of pravastatin therapy. Compared to the placebo group the plasma concentration of total cholesterol and phospholipids, free cholesterol and cholesterol esters, and plasma LDL-cholesterol and LDL-phospholipids were decreased during 6 months of pravastatin therapy. No changes in plasma VLDL-, HDL-, HDL2- or HDL3-cholesterol, phospholipids or triglycerides were observed in the pravastatin-treated patients. A decrease in the plasma level of apolipoprotein B and of LDL-apo B, but not of VLDL-apo B, was observed during pravastatin therapy; the plasma apolipoprotein AI and AII levels, as well as HDL2- and HDL3-apo AI and apo AII levels, however, remained unchanged. Plasma lipoprotein Lp(a) did not change during pravastatin therapy, while the plasma lecithin cholesterol acyltransferase activity (LCAT) increased. Compared to the placebo group the erythrocyte and platelet membrane cholesterol content was reduced in the pravastatin-treated patients. The intraerythrocyte and intraplatelet Na+ concentration was reduced during pravastatin administration, while the erythrocyte and platelet Na+/K+ pump activity was increased. However, the intraerythrocyte and intraplatelet K+, Mg2+, cytosolic Ca2+ concentration and water content as well as the erythrocyte Na+/Li+ countertransport and Na+/K+ cotransport activity and the Na+ and K+ leak were not changed during pravastatin treatment. Our data show that cholesterol lowering in hypercholesterolemic patients may result in a significant decrease in erythrocyte and platelet membrane cholesterol content. These changes in plasma membrane cholesterol are accompanied by an increase in the Na+ pump activity and a decrease in intracellular Na+ concentration. Whether these changes in membrane lipids and function observed during cholesterol lowering also occur in other cells remains to be further elucidated.
Lijnen
P
P
Department of Molecular and Cardiovascular Research, University of Leuven (KULeuven), Belgium.
Echevaría-Vázquez
D
D
Petrov
V
V
D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors; D000328:Adult; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001053:Apolipoproteins / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000097:blood*; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy; D008297:Male; D008563:Membrane Lipids / Q000097:blood*; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood; D010743:Phospholipids / Q000097:blood*; D017035:Pravastatin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D000214:Acyl Coenzyme A; D000924:Anticholesteremic Agents; D001053:Apolipoproteins; D004791:Enzyme Inhibitors; D008563:Membrane Lipids; D010743:Phospholipids; D014280:Triglycerides; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D000254:Sodium-Potassium-Exchanging ATPase; D017035:Pravastatin