Transcriptional activation of low density lipoprotein receptor gene by angiotensin-converting enzyme inhibitors and Ca(2+)-channel blockers involves protein kinase C isoforms.
The pharmacological potency of angiotensin-converting enzyme (ACE) inhibitors (lisinopril and enalaprilat) on the transcription of low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase genes was examined in human vascular smooth muscle cells and compared with the action of Ca(2+)-channel blockers (manidipine, verapamil, and diltiazem). Analogous to Ca(2+)-channel blockers, nanomolar concentrations of enalaprilat or lisinopril stimulated the synthesis of low density lipoprotein receptor mRNA and amplified the transcription induced by recombinant platelet-derived growth factor BB. In contrast to Ca(2+)-channel blockers, ACE inhibitors did not alter the transcription of the 3-hydroxy-3-methylglutaryl-CoA reductase gene. Platelet-derived growth factor BB stimulated the translocation of delta and epsilon isoforms of protein kinase C. Similar to Ca(2+)-channel blockers, ACE inhibitors reduced the translocation of delta and epsilon isoforms of protein kinase C. Furthermore, ACE inhibitors and Ca(2+)-channel blockers inhibited platelet-derived growth factor BB-induced transcription of c-fos and c-jun genes. The findings suggest that increased de novo synthesis of mRNA low density lipoprotein receptor apparently involves the participation of delta and epsilon isoforms of protein kinase C and transcription factors c-Fos and c-Jun.
Block
L H
LH
Department of Medicine, University of Vienna, Austria.
Keul
R
R
Crabos
M
M
Ziesche
R
R
Roth
M
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001011:Aorta / Q000502:physiology*; D015152:Blotting, Northern; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015342:DNA Probes; D005786:Gene Expression Regulation / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009838:Oligodeoxyribonucleotides; D015345:Oligonucleotide Probes; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D015342:DNA Probes; D007527:Isoenzymes; D009838:Oligodeoxyribonucleotides; D015345:Oligonucleotide Probes; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011973:Receptors, LDL; D011994:Recombinant Proteins; D012313:RNA; D006903:Hydroxymethylglutaryl CoA Reductases; D011493:Protein Kinase C