Possible role of parathyroid hormone-related protein as a proinflammatory cytokine in atherosclerosis

Background and Purpose - Parathyroid hormone - related protein ( PTHrP) is a vasodilator peptide. In addition, PTHrP appears to affect vascular growth and to be a mediator of inflammation in rheumatic and brain disorders. We examined the possible role of PTHrP in the inflammatory process in atherosclerosis Methods - We immunohistochemically analyzed the cellular localization of PTHrP, the type 1 PTH/PTHrP receptor (PTH1R), and monocyte chemoattractant protein-1 (MCP-1) in 26 human carotid atherosclerotic plaques. Results - The inflammatory region of plaques was characterized by high PTHrP, PTH1R, and MCP-1 immunostaining in relation to the cap (0.75 +/- 0.1 versus 0.29 +/- 0.04, 0.5 +/- 0.1 versus 0.25 +/- 0.05, 0.72 +/- 0.2 versus 0.29 +/- 0.05, respectively; P < 0.05). PTHrP and MCP-1 were colocalized in both resident and inflammatory cells in the plaque. Moreover, in cultured vascular smooth muscle cells (VSMC), PTHrP( 1 - 36) increased MCP-1 mRNA (3-fold at 6 hours) and MCP-1 protein (2.5-fold at 24 hours). This effect was inhibited by either PTHrP(7-34) or various protein kinase A inhibitors and by the nuclear factor-kappa B (NF-kappa B) inhibitor parthenolide. Furthermore, PTHrP( 1 - 36) elicited an increase in NF-kappa B activation in VSMC. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin inhibited the PTHrP(1 - 36) induction of both NF-kappa B activity and MCP-1 overexpression, and this was reversed by mevalonate. Conclusions - PTHrP appears to be a novel proinflammatory mediator in the atheroma lesion and may contribute to the instability of carotid atherosclerotic plaques. Our data provide a new rationale to understand the mechanisms involved in the beneficial effects of statins in atherosclerosis.