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- _4 value "Background: Parathyroid hormone-related protein (PTHrP) is a potent vasodilator, which also regulates vascular smooth muscle cell (VSMC) proliferation. Moreover, PTHrP overexpression has been correlated to the severity of coronary atherosclerosis, although the role of PTHrP in this disease remains to be elucidated.In addition,plaque rupture frequently takes place in the shoulder region, an area characterized by a high inflammatory content,although the mechanisms are not completely defined. Methods and Results: : We analyzed the cell composition, as well as the PTHrP and monocyte chemoattractant protein-1 (MCP-1) expression, in 22 human carotid atherosclerotic plaques, by immunohistochemistry. The inflammatory region of plaques was characterized by a high PTHrP and MCP-1 expression (20? 2 % vs 10 ?1 % and 14 ?2 vs 10?2 % of positive staining in the shoulder vs cap regions per mm2, respectively, p<0,05); moreover, both proteins were colocalized in the same cells of the plaque. In VSMC in vitro,N-terminal fragment of PTHrP, PTHrP (1-36), increased MCP-1 mRNA expression, peaking at 6h(3,3 ?0,3 fold vs basal;n=3; p<0,05; Northern blot). This effect was inhibited by the antagonist PTHrP (7-34) and by protein kinase A inhibitors (RpCAMPS and H89), as well as by the nuclear factor- kB (NF-kB) inhibitor parthenolide. Furthermore, PTHrP (1-36) induced an increase in NF-kB activation in VSMC, peaking at 90 minutes, as determined by electrophoretic mobility shift assay (EMSA). HMG-CoA reductase inhibitor, simvastatin, inhibited the effects of PTHrP (1-36) on both NF-kB activity and MCP-1 overexpression, and these effects were reversed by mevalonate. Conclusions: PTHrP may be a novel mediator involved in the recruitment of mononuclear cells into the atheroma lesion through the induction of MCP-1, and therefore contribute to the instability of atherosclerotic plaques.Our data also provide a new potential mechanism by which statins could exert its known antiinflammatory properties, and then contribute to plaque stabilization." provenance.
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