Possible role of parathyroid hormone-related protein as a proinflammatory cytokine in atherosclerosis.
OBJECTIVE
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-kappaB (NF-kappaB) inhibitor parthenolide. Furthermore, PTHrP(1-36) elicited an increase in NF-kappaB activation in VSMC. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin inhibited the PTHrP(1-36) induction of both NF-kappaB 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.
Martín-Ventura
José Luis
JL
Vascular Research Laboratory, Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
Ortego
Mónica
M
Esbrit
Pedro
P
Hernández-Presa
Miguel Angel
MA
Ortega
Luis
L
Egido
Jesús
J
D000368:Aged; D000818:Animals; D001161:Arteriosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000494:pharmacology; D036361:Peptide Hormones / Q000378:metabolism*; D011233:Precipitin Tests; D011506:Proteins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000096:biosynthesis; D012717:Sesquiterpenes / Q000494:pharmacology
D018932:Chemokine CCL2; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D016328:NF-kappa B; C473449:PTH1R protein, human; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D036361:Peptide Hormones; D011506:Proteins; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D012717:Sesquiterpenes; C079957:parathyroid hormone-related peptide (1-36); C002669:parthenolide