Lysosome inhibitors enhance the ability of cyclic AMP-elevating agents to induce the LDL receptor in human vascular smooth muscle cells.
In human vascular smooth muscle cells cyclic AMP elevation by forskolin increases synthesis of the LDL receptor by a mechanism which appears independent of sterol control. This increased receptor synthesis is further enhanced by chloroquine. Both forskolin and prostaglandin E1 increase the number of cell surface LDL receptors indicating that prostaglandins could exert physiological control over LDL metabolism. This effect is enhanced synergistically by chloroquine. The stimulation by forskolin of LDL receptor synthesis and expression leads to increased metabolism of apo-B and increased hydrolysis of LDL-borne cholesteryl ester. These effects of cyclic AMP on the activity of the LDL pathway are enhanced more than additively by preincubation with the reversible lysosomal inhibitor NH4Cl. Thus cyclic AMP causes up-regulation of the LDL receptor pathway resulting in increased rates of LDL metabolism but this effect can be damped or masked in cell culture by a cyclic AMP-sensitive lysosomal event, probably the acute stimulation of lysosomal cholesterol ester hydrolase.
Middleton
B
B
Department of Biochemistry, University of Nottingham Medical School, Queen's Medical Centre, England, U.K.
D000527:Alprostadil / Q000494:pharmacology*; D000643:Ammonium Chloride / Q000494:pharmacology*; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D004357:Drug Synergism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D011973:Receptors, LDL / Q000096:biosynthesis* / Q000302:isolation & purification
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D000643:Ammonium Chloride; D005576:Colforsin; D002738:Chloroquine; D000242:Cyclic AMP; D000527:Alprostadil