CLINICAL RESEARCH
C-Reactive Protein Induces Matrix Metalloproteinase-1 and -10 in Human Endothelial Cells
Implications for Clinical and Subclinical Atherosclerosis
Ines Montero, BS*, ,
Josune Orbe, PhD*, ,
Nerea Varo, PhD,,
Oscar Beloqui, MD, PhD ,
José I. Monreal, MD, PhD,
José A. Rodríguez, PhD*,,
Javier Díez, MD, PhD,
Peter Libby, MD|| and
José A. Páramo, MD, PhD*,,*
* Laboratory of Atherosclerosis
Division of Cardiovascular Sciences
Internal Medicine
Biochemistry Laboratory, School of Medicine/University Clinic, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
|| D.W. Reynolds Foundation Cardiovascular Research Center of Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Manuscript received August 4, 2005;
revised manuscript received October 4, 2005,
accepted October 10, 2005.
* Reprint requests and correspondence: Dr. José Antonio Páramo, Laboratory of Atherosclerosis, Center for Applied Medical Research (CIMA), Avda Pio XII 55, 31008 Pamplona, Spain (Email: japaramo{at}unav.es).
OBJECTIVES: We examined the effect of C-reactive protein (CRP) on matrix metalloproteinase (MMP) and inhibitor expression in endothelial cells and in patients with clinical and subclinical atherosclerosis.
BACKGROUND: In addition to predicting atherosclerotic vascular disease, CRP may directly promote a proinflammatory/proatherosclerotic phenotype.
METHODS: Human umbilical vein endothelial cells (HUVECs) and aortic endothelial cells (HAECs) were incubated in the presence or absence of CRP (50 µg/ml). Microarray analysis, real-time polymerase chain reaction, immunological and activity assays for MMPs were performed. Specific inhibitors of mitogen-activated protein kinase pathway were used. The MMP-1 and -10 plasma levels were measured in apparently healthy subjects (n = 70). Immunolocalization of CRP, MMP-1, and MMP-10 was performed in human mammary arteries and carotid endarterectomy specimens.
RESULTS: C-reactive protein augmented MMP-1 and -10 messenger ribonucleic acid expression in HUVEC (p < 0.05) and HAEC (p < 0.01). C-reactive protein stimulation also increased MMP-1 and -10 protein in conditioned culture medium (p < 0.001), as well as MMP activity (p = 0.001). Specific inhibition of p38 or MEK abolished the CRP induction of the MMP-1, whereas MMP-10 induction blockade required the simultaneous inhibition of p38 and Jun N-terminal kinase pathways. Subjects with CRP values >3 mg/l (n = 37) had increased plasma MMP-1 and -10 (p < 0.05), the association being significant after adjustment for confounding variables (p = 0.04 and p = 0.008, respectively). The MMP-10 levels were elevated in subjects with higher carotid intima-media thickness (p = 0.009). Increased CRP and MMP-10 colocalized in endothelial layer and macrophage-rich areas in advanced atherosclerotic plaques.
CONCLUSIONS: Increased local and systemic CRP-related MMP activation might provide a link between inflammation and plaque vulnerability.
|
Abbreviations and Acronyms
| | BMI = body mass index | | CCA = common carotid arteries | | CRP = C-reactive protein | | EC = endothelial cell | | ERK = extracellular signal-regulated kinase | | HAEC = human aortic endothelial cell | | HUVEC = human umbilical vein endothelial cell | | IMT = intima-media thickness | | JNK = Jun N-terminal kinase | | MAPK = mitogen-activated protein kinases | | MMP = matrix metalloproteinase | | RT-PCR = reverse transcription-polymerase chain reaction | | TIMP = tissue inhibitor of metalloproteinase | | vWf = von Willebrand factor |
|
Related Article
-
C-Reactive Protein and the Vascular Endothelium: Implications for Plaque Instability
- Ishwarlal Jialal, Sridevi Devaraj, and Uma Singh
J. Am. Coll. Cardiol. 2006 47: 1379-1381.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
J. Orbe, J. Barrenetxe, J. A. Rodriguez, D. Vivien, C. Orset, W. C. Parks, T. P. Birkland, R. Serrano, A. Purroy, S. Martinez de Lizarrondo, et al.
Matrix Metalloproteinase-10 Effectively Reduces Infarct Size in Experimental Stroke by Enhancing Fibrinolysis via a Thrombin-Activatable Fibrinolysis Inhibitor-Mediated Mechanism
Circulation,
December 20, 2011;
124(25):
2909 - 2919.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Quillard, Y. Tesmenitsky, K. Croce, R. Travers, E. Shvartz, K. C. Koskinas, G. K. Sukhova, E. Aikawa, M. Aikawa, and P. Libby
Selective Inhibition of Matrix Metalloproteinase-13 Increases Collagen Content of Established Mouse Atherosclerosis
Arterioscler Thromb Vasc Biol,
November 1, 2011;
31(11):
2464 - 2472.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. N. Bhupathiraju and K. L. Tucker
Greater variety in fruit and vegetable intake is associated with lower inflammation in Puerto Rican adults
Am J Clin Nutr,
January 1, 2011;
93(1):
37 - 46.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. Bisoendial, S. M. Boekholdt, M. Vergeer, E. S. G. Stroes, and J. J. P. Kastelein
C-reactive protein is a mediator of cardiovascular disease
Eur. Heart J.,
September 1, 2010;
31(17):
2087 - 2091.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Orbe, J. A. Rodriguez, O. Calvayrac, R. Rodriguez-Calvo, C. Rodriguez, C. Roncal, S. Martinez de Lizarrondo, J. Barrenetxe, J. C. Reverter, J. Martinez-Gonzalez, et al.
Matrix Metalloproteinase-10 Is Upregulated by Thrombin in Endothelial Cells and Increased in Patients With Enhanced Thrombin Generation
Arterioscler Thromb Vasc Biol,
December 1, 2009;
29(12):
2109 - 2116.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. D. Norata, P. Marchesi, V. K. Pulakazhi Venu, F. Pasqualini, A. Anselmo, F. Moalli, I. Pizzitola, C. Garlanda, A. Mantovani, and A. L. Catapano
Deficiency of the Long Pentraxin PTX3 Promotes Vascular Inflammation and Atherosclerosis
Circulation,
August 25, 2009;
120(8):
699 - 708.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Sokal, M. Zembala, A. Radomski, A. Kocher, J. Pacholewicz, J. Los, E. Jedrzejczyk, M. Zembala, and M. Radomski
A differential release of matrix metalloproteinases 9 and 2 during coronary artery bypass grafting and off-pump coronary artery bypass surgery.
J. Thorac. Cardiovasc. Surg.,
May 1, 2009;
137(5):
1218 - 1224.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Maingrette, L. Li, and G. Renier
C-reactive protein enhances macrophage lipoprotein lipase expression
J. Lipid Res.,
September 1, 2008;
49(9):
1926 - 1935.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Paramo
A new favourable effect of cocoa on atherosclerosis?
Cardiovasc Res,
July 1, 2008;
79(1):
3 - 4.
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Singh, M. R. Dasu, P. G. Yancey, A. Afify, S. Devaraj, and I. Jialal
Human C-reactive protein promotes oxidized low density lipoprotein uptake and matrix metalloproteinase-9 release in Wistar rats
J. Lipid Res.,
May 1, 2008;
49(5):
1015 - 1023.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Y. Kassim, S. A. Gharib, B. H. Mecham, T. P. Birkland, W. C. Parks, and J. K. McGuire
Individual Matrix Metalloproteinases Control Distinct Transcriptional Responses in Airway Epithelial Cells Infected with Pseudomonas aeruginosa
Infect. Immun.,
December 1, 2007;
75(12):
5640 - 5650.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Sanz, P. R. Moreno, and V. Fuster
The Year in Atherothrombosis
J. Am. Coll. Cardiol.,
April 24, 2007;
49(16):
1740 - 1749.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. T. Miller, P. M. Ridker, P. Libby, and D. J. Kwiatkowski
Atherosclerosis: The Path From Genomics to Therapeutics
J. Am. Coll. Cardiol.,
April 17, 2007;
49(15):
1589 - 1599.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-W. Wu, H.-L. Kao, M.-F. Chen, B.-C. Lee, W.-Y. I. Tseng, J.-S. Jeng, K.-Y. Tzen, R.-F. Yen, P.-J. Huang, and W.-S. Yang
Characterization of Plaques Using 18F-FDG PET/CT in Patients with Carotid Atherosclerosis and Correlation with Matrix Metalloproteinase-1
J. Nucl. Med.,
February 1, 2007;
48(2):
227 - 233.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. N. DeMaria, O. Ben-Yehuda, G. K. Feld, G. S. Ginsburg, B. H. Greenberg, W. Y.W. Lew, J. A.C. Lima, A. S. Maisel, J. Narula, D. J. Sahn, et al.
Highlights of the Year in JACC 2006
J. Am. Coll. Cardiol.,
January 30, 2007;
49(4):
509 - 527.
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. M. Howard-Alpe, J. W. Sear, and P. Foex
Methods of detecting atherosclerosis in non-cardiac surgical patients; the role of biochemical markers
Br. J. Anaesth.,
December 1, 2006;
97(6):
758 - 769.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Fujii, S.-H. Li, P. E. Szmitko, P. W.M. Fedak, and S. Verma
C-Reactive Protein Alters Antioxidant Defenses and Promotes Apoptosis in Endothelial Progenitor Cells
Arterioscler Thromb Vasc Biol,
November 1, 2006;
26(11):
2476 - 2482.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, I. Jialal, B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, and I. Jialal
The Verdict Is Still Out
Circulation,
May 2, 2006;
113(17):
2128 - 2151.
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Jialal, S. Devaraj, and U. Singh
C-Reactive Protein and the Vascular Endothelium: Implications for Plaque Instability
J. Am. Coll. Cardiol.,
April 4, 2006;
47(7):
1379 - 1381.
[Full Text]
[PDF]
|
|
|
|
