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

Author(s):
Boekhorst, B.C.T.; Bovens, S.M.; Hellings, W.E.; Kraak, P.H. van der; Kolk, K.W.V. de; Vink, A.; Moll, F.L.; Oosterhout, M.F. van; Vries, J.P. de; Doevendans, P.A.; Goumans, M.J.; Kleijn, D.P. de; Echteld, C.J. van; Pasterkamp, G.; Sluijter, J.P.
Published
2011
Publication type
Article / Letter to editor

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.

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
Date issued
2011-02-28
Language
English
Is part of
Cardiovascular Research (2011), Vol. 89, no. 3, p. 680-688
hdl
1887/109029
doi
10.1093/cvr/cvq340