Ca(2+)-channel blockers modulate expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and low density lipoprotein receptor genes stimulated by platelet-derived growth factor.
The effects of Ca(2+)-channel blockers (amlodipine, nifedipine, nitrendipine, and verapamil) on expression of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (EC 1.1.1.88) and low density lipoprotein receptor (LDL-R) genes stimulated by recombinant platelet-derived growth factor BB isomer (PDGF-BB) were evaluated in human skin fibroblasts. The drugs enhanced expression of the LDL-R protein on the plasma membrane of the cells; in contrast, they inhibited expression of the HMG-CoA reductase gene. In addition, PDGF-BB-dependent stimulation of transcription of c-fos mRNA was inhibited also by the Ca(2+)-channel blockers. We conclude that PDGF-BB-dependent activation of the two genes is inhibited effectively by the Ca(2+)-channel blockers, at therapeutic concentrations, although they are unable to lower systemic cholesterol levels at these concentrations; however, they do modify responses of the two genes that are involved crucially in regulation of cellular cholesterol homeostasis.
Block
L H
LH
Department of Medicine, University of Freiburg, Federal Republic of Germany.
Matthys
H
H
Emmons
L R
LR
Perruchoud
A
A
Erne
P
P
Roth
M
M
D017311:Amlodipine; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D005796:Genes / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D007700:Kinetics; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology; D009568:Nitrendipine / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics*; D012867:Skin; D014158:Transcription, Genetic / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011973:Receptors, LDL; D017311:Amlodipine; D009568:Nitrendipine; D014700:Verapamil; D006903:Hydroxymethylglutaryl CoA Reductases; D009543:Nifedipine