Molecular MRI of murine atherosclerotic plaque targeting NGAL: a protein associated with unstable human plaque characteristics

B.C.M. te Boekhorst, S.M. Bovens, W.E. Hellings, P.H. van der Kraak, K.W. van de Kolk, A. Vink, F.L. Moll, M.F.M. van Oosterhout, J.P. de Vries, P.A.F.M. Doevendans, M.J. Goumans, D.P.V. de Kleijn, C.J.A. van Echteld, G. Pasterkamp, J.P.G. Sluijter

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Abstract

Aims Neutrophil gelatinase-associated lipocalin (NGAL) is an effector molecule of the innate immune system. One of its actions is the prolongation of matrix metalloproteinase-9 (MMP-9) activity by the formation of a degradation-resistant NGAL/MMP-9 complex. We studied NGAL in human atherosclerotic lesions and we examined whether NGAL could act as a target for molecular imaging of atherosclerotic plaques.

Methods and results Increased levels of NGAL and the NGAL/MMP-9 complex were associated with high lipid content, high number of macrophages, high interleukin-6 (IL-6) and IL-8 levels, and low smooth muscle cell content in human atherosclerotic lesions obtained during carotid endarterectomy (n = 122). Moreover, plaque levels of NGAL tended to be higher when intra-plaque haemorrhage (IPH) or luminal thrombus was present (n 77) than without the presence of IPH or thrombus (n 30). MMP-9 and -8 activities were strongly related to NGAL levels. The enhancement on magnetic resonance (MR) images of the abdominal aorta of ApoE(-/-)/eNOS(-/-) mice was observed at 72 h after injection of NGAL/24p3-targeted micelles. The specificity of these results was validated by histology, and co-localization of micelles, macrophages, and NGAL/24p3 was observed.

Conclusion NGAL is highly expressed in atheromatous human plaques and associated with increased MMP-9 activity. NGAL can be detected in murine atherosclerotic arteries using targeted high-resolution MR imaging. Therefore, we conclude that NGAL might serve as a novel imaging target for the detection of high-risk plaques.

Original languageEnglish
Pages (from-to)680-688
Number of pages9
JournalCardiovascular Research
Volume89
Issue number3
DOIs
Publication statusPublished - Feb 2011

Keywords

  • Atherosclerosis
  • Matrix metalloproteinases
  • Macrophages
  • Contrast agents
  • Molecular MRI
  • GELATINASE-ASSOCIATED LIPOCALIN
  • MATRIX METALLOPROTEINASES
  • NEUTROPHIL GELATINASE
  • CAROTID-ENDARTERECTOMY
  • MYOCARDIAL-INFARCTION
  • EPITHELIAL-CELLS
  • CONTRAST AGENTS
  • IN-VIVO
  • EXPRESSION
  • LESIONS

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