scholarly journals Non-Invasive Detection of Extracellular Matrix Metalloproteinase Inducer EMMPRIN, a New Therapeutic Target against Atherosclerosis, Inhibited by Endothelial Nitric Oxide

2018 ◽  
Vol 19 (10) ◽  
pp. 3248 ◽  
Author(s):  
Rafael Ramirez-Carracedo ◽  
Laura Tesoro ◽  
Ignacio Hernandez ◽  
Javier Diez-Mata ◽  
Marco Filice ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Extracellular Matrix ◽  
Therapeutic Target ◽  
Specific Binding ◽  
Plaque Formation ◽  
Extracellular Matrix Metalloproteinase Inducer ◽  
Binding Peptide ◽  
Non Invasive ◽  
Atheroma Plaque ◽  
Endothelial Nitric Oxide

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.

Abstract 19684: Nitric Oxide Protects From Cardiac Ischemia/reperfusion Damage by Blocking Activation of Extracellular Matrix Metalloproteinase Inducer EMMPRIN Through Binding to Caveolin3

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Irene Cuadrado ◽  
Ana M Martin ◽  
Marta Saura ◽  
Jose L Zamorano ◽  
Carlos Zaragoza
Keyword(s):  
Nitric Oxide ◽  
Extracellular Matrix ◽  
Matrix Metalloproteinase ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Dependent Manner ◽  
Cardiac Protection ◽  
High Frequency Ultrasound ◽  
Extracellular Matrix Metalloproteinase Inducer

Introduction: Nitric Oxide (NO) induces cardiac protection by still unknown mechanisms. We previously found that Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) is a target of NO during ischemia/reperfusion (IR). Hypothesis: EMMPRIN is glycosylated at different locations, and high glycosylated forms of EMMPRIN are required for matrix metalloproteinase downstream activation in several cell types. In hearts subject to IR NO may inhibit EMMPRIN glycosylation. Methods: A surgical model of coronary artery occlusion. Results: We found that iNOS null mice show high glycosylated (active) forms of EMMPRIN, whereas NO producing mice also show low glycosylated EMMPRIN. Likewise, NO producing mice exhibit a significant level of cardiac protection, as shown by increased left ventricle ejection fraction detected by high frequency ultrasound, and decreased area of infarction as shown by ex vivo TTC staining. To test whether low glycosylated forms of EMMPRIN may play a role in iNOS WT cardiac protection, we found that EMMPRIN binds to caveolin-3 in healthy hearts, however, I/R prompted the disruption of low glycosylated EMMPRIN from caveolin-3 in iNOS null mice in a time dependent manner whereas a significant low glycosylated portion of EMMPRIN remained bound to caveolin-3 in iNOS WT mice. To study this effect in more detail, we found that caveolin-3 binding to low glycosylated forms of EMMPRIN, prevents downstream EMMPRIN-mediated extracellular matrix degradation through matrix metalloproteinase activation. I/R damage resulted more severe in caveolin-3 null mice, where no low glycosylated EMMPRIN was detected after reperfusion. Conclusions: We show for the first time that caveolin-3 induces nitric oxide mediated cardiac protection by preventing glycosylation of EMMPRIN in mouse hearts.

Localization of endothelial nitric oxide synthase in the normal and failing human atrial myocardium

1996 ◽  
Vol 54 ◽  
pp. 786-787
Author(s):  
Chi-Ming Wei ◽  
Margarita Bracamonte ◽  
Shi-Wen Jiang ◽  
Richard C. Daly ◽  
Christopher G.A. McGregor ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Cardiac Tissues ◽  
Mammalian Tissues ◽  
End Stage Heart Failure ◽  
End Stage ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Nitric oxide (NO) is a potent endothelium-derived relaxing factor which also may modulate cardiomyocyte inotropism and growth via increasing cGMP. While endothelial nitric oxide synthase (eNOS) isoforms have been detected in non-human mammalian tissues, expression and localization of eNOS in the normal and failing human myocardium are poorly defined. Therefore, the present study was designed to investigate eNOS in human cardiac tissues in the presence and absence of congestive heart failure (CHF).Normal and failing atrial tissue were obtained from six cardiac donors and six end-stage heart failure patients undergoing primary cardiac transplantation. ENOS protein expression and localization was investigated utilizing Western blot analysis and immunohistochemical staining with the polyclonal rabbit antibody to eNOS (Transduction Laboratories, Lexington, Kentucky).

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