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CLINICAL RESEARCH: ATHEROSCLEROSIS

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, School of Medicine/University Clinic, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
Division of Cardiovascular Sciences, School of Medicine/University Clinic, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
Internal Medicine, School of Medicine/University Clinic, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
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

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