TRANSCRIPTIONAL ACTIVATION OF LOW-DENSITY-LIPOPROTEIN RECEPTOR GENE BY ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS AND CA2+-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 Ca2+-channel blockers (manidipine, verapamil, and diltiazem). Analogous to Ca2+-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 Ca2+-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 partial derivative and epsilon isoforms of protein kinase C. Similar to Ca2+-channel blockers, ACE inhibitors reduced the translocation of partial derivative and epsilon isoforms of protein kinase C. Furthermore, ACE inhibitors and Ca2+-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 partial derivative and epsilon isoforms of protein kinase C and transcription factors c-Fos and c-Jun.