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) inh ibitors (lisinopril and enalaprilat) on the transcription of low densi ty lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase g enes was examined in human vascular smooth muscle cells and compared w ith the action of Ca2+-channel blockers (manidipine, verapamil, and di ltiazem). 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 r ecombinant platelet-derived growth factor BB. In contrast to Ca2+-chan nel blockers, ACE inhibitors did not alter the transcription of the 3- hydroxy-3-methylglutaryl-CoA reductase gene. Platelet-derived growth f actor BB stimulated the translocation of partial derivative and epsilo n 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+-ch annel blockers inhibited platelet-derived growth factor BB-induced tra nscription of c-fos and c-jun genes. The findings suggest that increas ed de novo synthesis of mRNA low density lipoprotein receptor apparent ly involves the participation of partial derivative and epsilon isofor ms of protein kinase C and transcription factors c-Fos and c-Jun.