Non-Invasive Detection of Extracellular Matrix Metalloproteinase Inducer EMMPRIN, a New Therapeutic Target against Atherosclerosis, Inhibited by Endothelial Nitric Oxide.
Author: Ramírez Carracedo, Rafael; Tesoro Santos, Laura; Hernández, Ignacio; Díez Mata, Javier; Filice, Marco; Toro, Rocío; Rodríguez Piñero, Manuel; Zamorano, José Luis; Saura, Marta; Zaragoza Sánchez, Carlos
Abstract: Lack of endothelial nitric oxide causes endothelial dysfunction and circulating monocyte
infiltration, contributing to systemic atheroma plaque formation in arterial territories. Among the
different inflammatory products, macrophage-derived foam cells and smooth muscle cells synthesize
matrix metalloproteinases (MMPs), playing a pivotal role in early plaque formation and enlargement.
We found increased levels of MMP-9 and MMP-13 in human endarterectomies with advanced
atherosclerosis, together with significant amounts of extracellular matrix (ECM) metalloproteinase
inducer EMMPRIN. To test whether the absence of NO may aggravate atherosclerosis through
EMMPRIN activation, double NOS3/apoE knockout (KO) mice expressed high levels of EMMPRIN
in carotid plaques, suggesting that targeting extracellular matrix degradation may represent a new
mechanism by which endothelial NO prevents atherosclerosis. Based on our previous experience,
by using gadolinium-enriched paramagnetic fluorescence micellar nanoparticles conjugated with AP9
(NAP9), an EMMPRIN-specific binding peptide, magnetic resonance sequences allowed non-invasive
visualization of carotid EMMPRIN in NOS3/apoE over apoE control mice, in which atheroma plaques
were significantly reduced. Taken together, these results point to EMMPRIN as a new therapeutic
target of NO-mediated protection against atherosclerosis, and NAP9 as a non-invasive molecular tool
to target atherosclerosis.
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