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.
Highlights
In the absence of endothelial NO, vascular endothelial cells become dysfunctional, playing a significant role in the pathogenesis of atherosclerosis
The levels of matrix metalloproteinases (MMPs)-9, MMP-13, and EMMPRIN were determined by immunohistochemistry in human crossed sections of carotid endarterectomy specimens, showing extensive atherosclerosis, as shown by hematoxylin/eosin, and Masson Trichrome staining (Figure 1A)
Extensive expression of EMMPRIN, MMP-9 and MMP-13 was detected in smooth muscle cells and foam cells, while EMMPRIN was expressed in endothelial cells of vascularized plaques (Figure 1C), when compared to the levels found in healthy control mammary arteries (Figure 1D), which suggest that EMMPRIN may contribute to the extension of atheroma plaque
Summary
In the absence of endothelial NO, vascular endothelial cells become dysfunctional, playing a significant role in the pathogenesis of atherosclerosis. The CyPA/EMMPRIN complex leads to platelet activation, adhesion, thrombus formation [9], and foam cell differentiation [10], playing a critical role in plaque progression and vulnerability [11]. An efficient alternative including smaller binding molecules, may represent a promising approach In this regard, paramagnetic micelles have been used to target specific proteins present in several pathophysiological conditions, including EMMPRIN, as we did for non-invasive visualization by molecular magnetic resonance imaging (MRI), finding a significant reduction of the left ventricle necrotic area, in murine and porcine models of acute myocardial infarction [15,16]. We used the same paramagnetic micelles for in vivo non-invasive visualization of EMMPRIN in atherosclerotic apoE and NO3/apoE double null mice, to evaluate the hypothesis that targeted inhibition of EMMPRIN may represent a new mechanism elicited by NO against atherosclerosis
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