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

Abstract

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.