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.


RESULTS
Atherosclerosis was induced in rabbits by femoral endothelial dessication and atherogenic diet. After 2 weeks, animals were randomized to receive either 5mg/(kgd) 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 (0.125-0.5mg/mL) increased PTHrP expression. This effect was prevented by preincubation with simvastatin (1micromol/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.
Martin-Ventura
Jose Luis
JL
Vascular Research Laboratory, Fundación Jiménez Díaz (Capio Group) and Autónoma University, Madrid, Spain.
Blanco-Colio
Luis Miguel
LM
Aparicio
Cesar
C
Ortega
Luis
L
Esbrit
Pedro
P
Egido
Jesús
J
D000818:Animals; D050197:Atherosclerosis / Q000139:chemically induced / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism* / Q000633:toxicity; D008264:Macrophages; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D011817:Rabbits; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D044162:Parathyroid Hormone-Related Protein; D011106:Polyisoprenyl Phosphates; D034741:RNA, Small Interfering; D044168:Receptor, Parathyroid Hormone, Type 1; D019821:Simvastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid