Published online before print June 12, 2003, doi: 10.1161/01.STR.0000078371.00577.76
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2003;34:1783.)
© 2003 American Heart Association, Inc.
Original Contributions |
Possible Role of Parathyroid Hormone–Related Protein as a Proinflammatory Cytokine in Atherosclerosis
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.
Correspondence to Jesús Egido, MD, Vascular Research Laboratory, Fundación Jiménez Díaz, Avenida Reyes Católicos 2, 28040 Madrid, Spain. 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
This article has been cited by other articles:
 |
|
 |
|
  J. L. Martin-Ventura, J. Madrigal-Matute, B. Munoz-Garcia, L. M. Blanco-Colio, M. Van Oostrom, G. Zalba, A. Fortuno, C. Gomez-Guerrero, L. Ortega, A. Ortiz, et al. Increased CD74 expression in human atherosclerotic plaques: contribution to inflammatory responses in vascular cells Cardiovasc Res, August 1, 2009; 83(3): 586 - 594. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ortiz-Munoz, J. L. Martin-Ventura, P. Hernandez-Vargas, B. Mallavia, V. Lopez-Parra, O. Lopez-Franco, B. Munoz-Garcia, P. Fernandez-Vizarra, L. Ortega, J. Egido, et al. Suppressors of Cytokine Signaling Modulate JAK/STAT-Mediated Cell Responses During Atherosclerosis Arterioscler Thromb Vasc Biol, April 1, 2009; 29(4): 525 - 531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Meziani, A. Tesse, S. Welsch, H. Kremer, M. Barthelmebs, R. Andriantsitohaina, F. Schneider, and A. Gairard Expression and Biological Activity of Parathyroid Hormone-Related Peptide in Pregnant Rat Uterine Artery: Any Role for 8-Iso-Prostaglandin F2{alpha}? Endocrinology, February 1, 2008; 149(2): 626 - 633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Wang, M. J. Pencina, S. L. Booth, P. F. Jacques, E. Ingelsson, K. Lanier, E. J. Benjamin, R. B. D'Agostino, M. Wolf, and R. S. Vasan Vitamin D Deficiency and Risk of Cardiovascular Disease Circulation, January 29, 2008; 117(4): 503 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. S. Mullenix, S. R. Steele, M. J. Martin, B. W. Starnes, and C. A. Andersen C-reactive Protein Level and Traditional Vascular Risk Factors in the Prediction of Carotid Stenosis Arch Surg, November 1, 2007; 142(11): 1066 - 1071. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Agouni, C. Sourbier, S. Danilin, S. Rothhut, V. Lindner, D. Jacqmin, J.-J. Helwig, H. Lang, and T. Massfelder Parathyroid hormone-related protein induces cell survival in human renal cell carcinoma through the PI3K Akt pathway: evidence for a critical role for integrin-linked kinase and nuclear factor kappa B Carcinogenesis, September 1, 2007; 28(9): 1893 - 1901. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Rashid, J. Bernheim, J. Green, and S. Benchetrit Cardiovascular Events and Parathyroid Hormone--Suggestion of a Further Link J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1023 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Lopez-Franco, P. Hernandez-Vargas, G. Ortiz-Munoz, G. Sanjuan, Y. Suzuki, L. Ortega, J. Blanco, J. Egido, and C. Gomez-Guerrero Parthenolide Modulates the NF-{kappa}B-Mediated Inflammatory Responses in Experimental Atherosclerosis Arterioscler Thromb Vasc Biol, August 1, 2006; 26(8): 1864 - 1870. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ortega, D. Ramila, J. A. Ardura, V. Esteban, M. Ruiz-Ortega, A. Barat, R. Gazapo, R. J. Bosch, and P. Esbrit Role of Parathyroid Hormone-Related Protein in Tubulointerstitial Apoptosis and Fibrosis after Folic Acid-Induced Nephrotoxicity J. Am. Soc. Nephrol., June 1, 2006; 17(6): 1594 - 1603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kimmel, D. M. Alscher, R. Dunst, N. Braun, C. Machleidt, T. Kiefer, C. Stulten, H. van der Kuip, C. Pauli-Magnus, U. Raub, et al. The role of micro-inflammation in the pathogenesis of uraemic pruritus in haemodialysis patients Nephrol. Dial. Transplant., March 1, 2006; 21(3): 749 - 755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Godler, A. N. Stein, O. Bakharevski, M. M. L. Lindsay, and P. F. J. Ryan Parathyroid hormone-related peptide expression in rat collagen-induced arthritis Rheumatology, September 1, 2005; 44(9): 1122 - 1131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Somjen, Y. Weisman, F. Kohen, B. Gayer, R. Limor, O. Sharon, N. Jaccard, E. Knoll, and N. Stern 25-Hydroxyvitamin D3-1{alpha}-Hydroxylase Is Expressed in Human Vascular Smooth Muscle Cells and Is Upregulated by Parathyroid Hormone and Estrogenic Compounds Circulation, April 5, 2005; 111(13): 1666 - 1671. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Parenti, L. Bellik, L. Brogelli, S. Filippi, and F. Ledda Endogenous VEGF-A is responsible for mitogenic effects of MCP-1 on vascular smooth muscle cells Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1978 - H1984. [Abstract] [Full Text] [PDF]
|
|