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(Circulation. 2004;110:177-185.)
© 2004 American Heart Association, Inc.

Original Articles

Parathyroid Hormone–Related Protein as a Regulator of pRb and the Cell Cycle in Arterial Smooth Muscle

Nathalie Fiaschi-Taesch, PhD; Karen K. Takane, PhD; Sophia Masters, BS; Juan Carlos Lopez-Talavera, MD, PhD; Andrew F. Stewart, MD

From the Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pa.

Correspondence to Nathalie Fiaschi-Taesch, PhD, Research Associate, Division of Endocrinology and Metabolism, BST E-1140, Endocrinology, University of Pittsburgh School of Medicine, 3550 Terrace St, Pittsburgh PA 15213. E-mail taeschn{at}msx.dept-med.pitt.edu

Received December 20, 2002; de novo received September 26, 2003; revision received March 9, 2004; accepted March 22, 2004.

Background— Parathyroid hormone–related protein (PTHrP), a normal product of arterial vascular smooth muscle (VSM), contains a nuclear localization signal (NLS) and at least 2 translational initiation sites, one that generates a conventional signal peptide and one that disrupts the signal peptide. These unusual features allow PTHrP either to be secreted in a paracrine/autocrine fashion, and thereby to inhibit arterial smooth muscle proliferation, or to be retained within the cytosol and to translocate into the nucleus, thereby serving as an intracrine stimulator of smooth muscle proliferation.

Methods and Results— Here, we demonstrate 2 important findings. First, PTHrP dramatically increases the percentage of VSM cells in the S and in G₂/M phases of the cell cycle. These effects require critical serine and threonine residues at positions Ser¹¹⁹, Ser¹³⁰, Thr¹³², and Ser¹³⁸ in the carboxy-terminus of PTHrP and are associated with the phosphorylation of the key cell cycle checkpoint regulator retinoblastoma protein, pRb. Second, because PTHrP devoid of the NLS serves as an inhibitor of VSM proliferation, we hypothesized that local delivery of NLS-deleted PTHrP to the arterial wall at the time of angioplasty might prevent neointimal hyperplasia. As hypothesized, using a rat carotid angioplasty model, adenoviral delivery of NLS-deleted PTHrP completely abolished the development of the neointima after angioplasty.

Conclusions— PTHrP interacts with key cell cycle regulatory pathways within the arterial wall. Moreover, NLS-deleted PTHrP delivered to the arterial wall at the time of angioplasty seems to have promise as an agent that could reduce or eliminate the neointimal response to angioplasty.

Key Words: muscle, smooth • proteins • neointima • restenosis • angioplasty

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