CLINICAL RESEARCH
Pregnancy-Associated Plasma Protein-A Is Markedly Expressed by Monocyte-Macrophage Cells in Vulnerable and Ruptured Carotid Atherosclerotic Plaques
A Link Between Inflammation and Cerebrovascular Events
Giuseppe Sangiorgi, MD, FESC*,*,
Alessandro Mauriello, MD ,
Elena Bonanno, MD,
Claus Oxvig, PhD¶,
Cheryl A. Conover, MD ,
Michael Christiansen, MD#,
Santi Trimarchi, MD ,
Vincenzo Rampoldi, MD,
David R. Holmes, Jr, MDFACC||,
Robert.S. Schwartz, MD, FACC** and
Luigi Giusto Spagnoli, MD
* Cardiovascular Disease
Vascular Surgery, Istituto Policlinico San Donato, San Donato Milanese, Milan, Italy
Department of Pathology, University of Rome Tor Vergata, Rome, Italy
Endocrinology Research Unit
|| Department of Cardiovascular Disease, Mayo Clinic and Foundation, Rochester, Minnesota
¶ Department of Molecular and Structural Biology, University of Aarhus, Aarhus, Denmark
# Department of Clinical Biochemestry, Staten Serum Institute, Copenhagen, Denmark
** Department of Cardiovascular Disease, Minneapolis Heart Foundation, Minneapolis, Minnesota
Manuscript received August 22, 2005;
revised manuscript received September 27, 2005,
accepted November 1, 2005.
* Reprint requests and correspondence: Dr. Giuseppe Sangiorgi, Emo Centro Cuore Columbus, Via Buonarroti 48, 20145 Milan, Italy (Email: sangiorgi{at}emocolumbus.it).
OBJECTIVES: The study aim was to evaluate serologic expression of pregnancy-associated protein-A (PAPP-A) in patients affected by cerebrovascular accidents and to correlate it with histopathologic carotid plaque complexity.
BACKGROUND: Little is known about PAPP-A expression in carotid atherosclerotic disease and whether this protein represents a marker of plaque vulnerability also in carotid district.
METHODS: Seventy-two carotid plaques from patients submitted to surgical endarterectomy (19 who suffered a major stroke, 24 transient ischemic attack, and 29 asymptomatic) were evaluated. Serologic PAPP-A levels were determined by enzyme-linked immunoadsorbent assay. Plaques were divided in three groups based on histology: 1) stable (n = 38); 2) vulnerable (n = 13); 3) ruptured with thrombus (n = 14). Immunohistochemical staining for PAPP-A, smooth muscle cells, macrophages, and T-lymphocytes was performed in all cases. Real-time polymerase chain reaction assessed local PAPP-A production, and double immunofluorescence confocal microscopy (ICM) characterized cell type expressing PAPP-A.
RESULTS: Pregnancy-associated protein-A (serologic values were 4.02 ± 0.18 mIU/l in Group 1, 7.43 ± 0.97 mIU/l in Group 2, and 6.97 ± 0.75 mIU/l in Group 3 [1 vs. 3, p = 0.01; 1 vs. 2, p = 0.004; 2 vs. 3, p = 0.71, respectively]). Pregnancy-associated protein-A (expression showed a mean score value of 0.62 ± 0.06 for stable plaques, 2.54 ± 0.14 for vulnerable plaques, and 2.71 ± 0.12 for ruptured plaques [1 vs. 2, p = 0.001; 1 vs. 3, p = 0.001; 2 vs. 3, p = 0.37, respectively]). Real-time polymerase chain reaction demonstrated local messenger ribonucleic acid PAPP-A production, and double ICM confirmed monocyte/macrophage expression of PAPP-A in Groups 2 and 3 but not Group 1.
CONCLUSIONS: This study suggests that PAPP-A is a marker of carotid plaque destabilization and rupture. Further studies are necessary to determine if PAPP-A can represents a new target for stratifying the risk of cerebrovascular events.
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Abbreviations and Acronyms
| | CT = computed tomography | | FITC = streptavidin-fluorescin conjugate | | hsCRP = high-sensitivity C-reactive protein | | ICM = immunofluorescence confocal microscopy | | MMPs = serum matrix metalloproteinases | | NASCET = North American Symptomatic Carotid Endarterectomy Trial | | PAPP-A = pregnancy-associated protein-A | | RT-PCR = quantitative real-time polymerase chain reaction | | TIA = transient ischemic attack |
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