LDL induces parathyroid hormone-related protein expression in vascular smooth muscle cells: Modulation by simvastatin

Background: Parathyroid hormone-related protein (PTHrP) is overexpressed in atherosclerotic plaques by unknown mechanisms. We have examined here the putative mechanism(s) responsible for this overexpression in the atherosclerotic lesion and its potential modulation by simvastatin, both in vitro and in vivo. Methods and results: Atherosclerosis was induced in rabbits by femoral endothelial dessication and atherogenic diet. After 2 weeks, animals were randomized to receive either 5 mg/(kg d) simvastatin (n = 7) or no treatment (n = 6) during 4 additional weeks. An increase in PTHrP immunostaining was observed in atherosclerotic lesions of hyperlipidemic rabbits, which was significantly reduced by simvastatin. However, PTH/PTHrP type 1 receptor staining was similar in both groups. In cultured vascular smooth muscle cells (VSMCs), atherogenic concentrations of native LDL (0.125-0.5 mg/mL) increased PTHrP expression. This effect was prevented by preincubation with simvastatin (1 mu mol/L) and was reversed by mevalonate, geranylgeranylpyrophosphate and, to a lesser extent, by farnesylpyrophosphate. Moreover, in transfection studies, we showed that RhoA appears to participate in the mechanism whereby LDL induces PTHrP in VSMC. Finally, native LDL-induced VSMC growth and this mitogenic effect was blocked by PTHrP silencing. Conclusions: LDL might be responsible for PTHrP overexpression in atherosclerotic plaques of hyperlipidemic rabbits. The inhibition of this effect by simvastatin provides further insights into the mechanisms of action of statins. (C) 2008 Elsevier Ireland Ltd. All rights reserved.