Published Online
on June 12, 2003

A more recent version of this article appeared on July 1, 2003

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Submitted on February 10, 2003
Accepted on February 26, 2003

Possible Role of Parathyroid Hormone-Related Protein as a Proinflammatory Cytokine in Atherosclerosis

José Luis Martín-Ventura BS; Mónica Ortego PhD; Pedro Esbrit PhD; Miguel Angel Hernández-Presa PhD; Luis Ortega MD; and Jesús Egido MD^*

From the Vascular Research Laboratory (J.L.M-V., M.O., M.A.H-P., J.E.) and Bone and Mineral Research Laboratory (P.E.), Fundación Jiménez Díaz, Autónoma University; and Department of Pathology, Hospital Clínico San Carlos (L.O.), Madrid, Spain.

^* To whom correspondence should be addressed. E-mail: jegido{at}fjd.es.

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-B (NF-B) inhibitor parthenolide. Furthermore, PTHrP(1-36) elicited an increase in NF-B activation in VSMC. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin inhibited the PTHrP(1-36) induction of both NF-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. \

Key words: atherosclerosis • carotid arteries • inflammation • monocyte chemoattractant protein-1 • parathyroid hormone-related protein

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